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TAG HIV Basic Science, Vaccines, and Cure Project Blog

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By Richard Jefferys, Project Director

Conference Catch Up: HIV Cure Research
11/19/19 - A number of conferences and workshops related to HIV cure research have taken place over the past several months, many of which can be viewed or learned about online. Links and some brief reports from four events are provided below. READ MORE

Case Report from the First Clinical Trial of CRISPR-Edited Stem Cells in People with HIV and Cancers
10/24/19 - One of the ways TAG keeps track of developments in HIV cure research is by maintaining an online listing of clinical research culled from trial registries (primarily In May 2017, a research group in China registered the first human HIV trial involving the CRISPR/Cas9 gene editing system—a technology that has generated considerable excitement and attention due to promising results in small animal models. Last month in the New England Journal of Medicine, the researchers published a case report describing outcomes in a study participant (presumably the first individual enrolled). READ MORE

Tracing the Formation of the HIV Reservoir
10/22/19 - In a previous report from the AIDS 2018 conference in Amsterdam, I briefly covered a presentation by Sarah Joseph from the University of North Carolina suggesting that the bulk of the persistent, replication-competent HIV reservoir is formed around the time that antiretroviral therapy (ART) is initiated. Details of the study have now been published in Science Translational Medicine, and Joseph and colleagues have also outlined how the findings might be exploited therapeutically in a separate open access paper in Frontiers in Immunology. READ MORE

Distinguishing Potential Mechanisms of HIV Persistence
10/11/19 - For researchers attempting to develop a cure for HIV infection, it’s important to understand the mechanisms by which the virus persists in the body despite suppression of viral load to undetectable levels by ART. Debate has centered around two possibilities that aren’t necessarily exclusive:

  • HIV continues to replicate at low levels in body tissues that ART drugs may not penetrate well (often referred to as sanctuary sites).
  • Cells with HIV integrated into their genetic code—latently infected cells—persist and proliferate even though ART has shut down virus replication.

In recent years, evidence has accumulated indicating that, in most people who are adherent to ART, HIV replication is completely suppressed. A new report in the journal Science Advances adds to this evidence by analyzing individuals in receipt of long-term ART. The results support the increasing research focus on the persistence and proliferation of HIV-infected cells as the major obstacle to a cure, a topic addressed by several other recently published papers. READ MORE

Widely Publicized Report Associating the CCR5-Δ32 Mutation with Reduced Longevity is Retracted
10/9/19 - In June of this year, a short paper was published in the journal Nature Medicine reporting that individuals homozygous for the CCR5-∆32 mutation showed a 21% increase in the rate of all-cause mortality compared to those without the mutation (or heterozygotes, who inherit the mutation from one parent). The senior author, Rasmus Nielsen, stated to the Wall Street Journal that this would equate to a nearly two-year shortening of lifespan on average. The findings were the subject of hundreds of media articles, largely because they came on the heels of a misguided and completely unethical experiment in which the CCR5 gene was edited in two embryos, leading to the birth of genetically altered twins. Questions were also raised about possible relevance to HIV cure research studies that attempt to ablate CCR5 expression with gene therapies. Yesterday, Nature Medicine published a notice that the paper has been retracted. READ MORE

Selected Highlights from CROI 2019
4/10/19 - The 2019 Conference on Retroviruses and Opportunistic Infections (CROI) took place in Seattle from March 3rd-7th. The major news on the cure research front was the possibility of two additional cases similar to Timothy Ray Brown, who for the past 12 years has been the only individual considered cured of HIV infection (TAG issued a statement offering our perspective). Other notable reports included the first results from a study using CRISPR/Cas9 to target latent SIV in macaques and a novel insight into the source of residual viral load in people on ART. Immediately preceding the conference, TAG joined with multiple other organizations to co-sponsor the annual pre-CROI community HIV cure research workshop; slides and video from the event are available online. READ MORE

The Influence of Nef Protein Function on HIV Reservoir Size
1/15/19 - A paper published in the Journal of Virology on January 2nd reports that the nefarious activities of HIV’s Nef protein can influence the size of the persistent viral reservoir in people on ART. Nef is known to be able to shield HIV-infected cells from recognition by the immune system, and Fredrick Omondi and colleagues found that this capacity correlated with measures of the HIV reservoir in a group of early-treated individuals assessed after 48 weeks of ART. The researchers also uncovered evidence that HIV reservoir size differed depending on viral subtype, likely partly due to between-subtype variation in the Nef protein. READ MORE

Significant Effects of a TLR7 Agonist Plus Broadly Neutralizing Antibody in the SHIV/Macaque Model
10/25/18 - Among the most newsworthy presentations at CROI 2018 earlier this year was Dan Barouch’s description of a study involving a toll-like receptor 7 (TLR7) agonist combined with a broadly neutralizing antibody (bNAb) in SHIV-infected macaques (see contemporary coverage by AIDSMap, i-Base and POZ Magazine). The results have now been published in the journal Nature. READ MORE

Combining Broadly Neutralizing Antibodies Shows Promise
10/12/18 - At CROI 2017, Michel Nussenzweig from Rockefeller University presented evidence that early administration of a short course of two broadly neutralizing antibodies (bNAbs)—3BNC117 and 10-1074—led to prolonged immunological control of SHIV viral load in macaques. The study was subsequently published in Nature. At the end of last month, results from the first human trials of the same dual bNAb regimen were announced in papers in Nature and Nature Medicine. READ MORE

2018 NIAID Strategies for an HIV Cure Meeting
10/9/18 - The biannual National Institute of Allergy and Infectious Diseases (NIAID) Strategies for an HIV Cure Meeting kicks off tomorrow, October 10, at 8:30am US Eastern Time and continues until Friday at 12:30pm. The agenda is available online. For those unable to attend in person the entire event is being made available for viewing via the National Institutes of Health videocast website (see the upcoming events link).

Post-AIDS 2018 Updates on HIV Cure Research
9/19/18 - In the aftermath of the 22nd International AIDS Conference (AIDS 2018), which took place in Amsterdam in July, there has been some reflecting on the challenges facing the HIV cure research field. The presentations that garnered the most news coverage described disappointing study results, but there were also nuggets of novelty and encouragement to be found amidst the sea of data on offer (see previous post for links to relevant conference sessions, many of which now have video and/or slides available). READ MORE

Studying HIV Persistence in Liver Macrophages
9/12/18 - The major reservoir of HIV that persists despite ART is contained in long-lived memory CD4 T cells. Whether other cell types, particularly macrophages, can harbor a reservoir of replication-competent HIV—and thus contribute to viral load rebound if ART is interrupted—remains uncertain, and a matter of some controversy among scientists. The question is important, because identifying and eliminating virus reservoirs is a central plank of the research effort to cure HIV infection. In a new paper in the Journal of Clinical Investigation (available open access), Abraham J. Kandathil and colleagues investigate whether human liver macrophages—which they note comprise up to 90% of all tissue macrophages—can sequester infectious HIV in people on ART. READ MORE

HIV Cure-Related Research at AIDS 2018
7/19/18 - Workshops, sessions and presentations related to HIV cure research at the upcoming AIDS 2018 conference in Amsterdam. 

Elite Controllers: Sex Differences and Factors Associated with Loss of Immune Control
3/14/18 - Over the past few months, several interesting papers addressing elite control of HIV infection have seen publication. The ability of elite controllers to maintain undetectable viral loads and relatively preserved CD4 T cell counts in the absence of ART has led them to be proposed as a model for a functional cure of HIV infection. But there is also evidence that many elite controllers exhibit elevated levels of inflammation compared to HIV-negative counterparts, and eventually experience disease progression, leading some researchers to call this proposition into question. The uncertain relevance of elite control to HIV cure research is prompting studies that attempt to parse the factors distinguishing individuals who preserve elite controller status from those who ultimately progress. READ MORE

Assessing Antiretroviral Therapy Interruptions in HIV Cure Research
2/22/18 - Last month, researchers from the Laboratory of Immunoregulation at the National Institute of Allergy and Infectious Diseases (NIAID) published a paper in PLoS Pathogens addressing the use of antiretroviral therapy (ART) interruptions in HIV cure research. The joint lead authors were Katherine E. Clarridge and Jana Blazkova, and the focus of the study was on the effects of an analytical treatment interruption (ATI) performed during a clinical trial of the broadly neutralizing antibody VRC01. The main results offer reassurance that the ATI had no long-term negative effects for participants—as articulated in an accompanying NIAID press release titled NIH Study Supports Use of Short-Term HIV Treatment Interruption in Clinical Trials—but there are some possible safety concerns that the data does not address. READ MORE

Recruiting Natural Killer Cells to Target HIV Persistence
1/18/18 - An important goal in HIV cure research is the identification of immune responses that might be induced or enhanced to promote clearance of virus-infected cells. The main focus of this work has been on adaptive immunity—components of the immune system that can specifically recognize HIV, which include CD4 T cells, CD8 T cells, B cells and antibodies. But there is growing interest in cells considered part of the innate immune system, particularly natural killer (NK) cells. NK cells have the potential to destroy virus-infected cells by several mechanisms, including the identification of generic signs of cellular distress or infection, or via antibody-mediated recruitment to a target cell (known as antibody-dependent cellular cytotoxicity/ADCC). READ MORE

New Data on Identifying and Targeting the Latent HIV Reservoir
1/17/18 - Several recently presented and published studies offer potentially important new data relevant to efforts to identify cells containing latent HIV and target them for elimination. READ MORE

Update on AAV Vectors as Delivery Vehicles for Broadly Neutralizing Antibodies: Ron Desrosiers and the Miami Macaque
12/14/17 - The idea of using adeno-associated virus (AAV) as a vehicle to deliver genes encoding anti-HIV broadly neutralizing antibodies (bNAbs) has been around for some time, and has been covered a number of times previously on the blog (e.g. see posts from May 2009 and January 2013). The approach was first developed by Phil Johnson as a possible way of circumventing the challenges associated with inducing broadly neutralizing antibodies using traditional vaccines. AAVs primarily take up residence in muscle tissue and can act as a factory for producing proteins encoded by genes inserted into the AAV genome. This past Tuesday evening at the HIV Persistence Workshop in Miami, the researcher Ron Desrosiers presented an update on efforts to deliver bNAbs with AAV, including the intriguing tale of a macaque in which the method appeared to have a profound therapeutic effect. READ MORE

Additional Remission Cases Published
12/5/17 - Two recent case reports of temporary HIV remission, first presented at this year’s CROI and IAS conferences, have now been published in the open access journal PLoS Medicine. READ MORE

HIV Latency: Trapped in Transition, Lurking in Treg
11/16/17 - The question of how HIV latency is typically established in long-lived memory CD4 T cells has yet to be fully resolved. One theory is that latency occurs when HIV infects a CD4 T cell that is in the process of transitioning from an activated state to a resting state, but direct evidence has been lacking. A new paper from the research group of Robert Siliciano, published in the journal Immunity, provides experimental support for this model of HIV latency initiation. READ MORE

Locking Down Latent HIV
11/2/17 - Strategies for dealing with the reservoir of latent HIV that persists despite antiretroviral therapy (ART) have primarily focused on awakening the virus from its dormant state. But Susana Valente and colleagues from the Scripps Research Institute in Florida are taking a different tack, flipping the idea of latency reversal on its head. Their approach—which they have dubbed block and lock—involves trying to imprison latent HIV in a way that prevents it from ever reactivating. The latest work by Valente’s group was published recently in the open access journal Cell Reports. READ MORE

Estimating the Total Size of the HIV Reservoir
10/30/17 - A paper published earlier this month in Nature Medicine by Jake Estes and colleagues addresses the difficult challenge of attempting to define the distribution and total size of the persistent HIV reservoir. The researchers employed a variety of tests to measure viral RNA and DNA—including new imaging techniques they have developed named RNAscope and DNAscope—in multiple tissues from untreated or ART-treated macaques (infected with SIVmac251, SIVmac239 or SHIV) as well as lymph node and rectal tissue samples from a cohort of 20 individuals on ART in Kampala, Uganda. READ MORE

Effects of the Anti-Inflammatory Antibody Canakinumab on Heart Disease and Cancer: Implications for HIV?
10/12/17 - Inflammation is increasingly recognized as an immunological double-edged sword: it contributes importantly to the response to infection, but can also cause serious collateral damage to the body—particularly when persistent—and has been implicated as potentially contributing to multiple conditions, including heart disease and cancers. Researchers have found that the anti-inflammatory effects of statin drugs contribute to their beneficial effects against cardiovascular disease, but because statins also reduce cholesterol it has not been possible to disentangle the relative importance of these two potential mechanisms of action. READ MORE

2017 IAS HIV Cure & Cancer Forum
9/29/17 - The IAS HIV Cure & Cancer Forum was held at the renowned cancer research center Institut Curie in Paris on July 22 & 23 of this year. A report from the meeting, authored by Genevieve E. Martin, José Alcami, Jean-Phillipe Spano and Anna Laura Ross, has just been published in the open access Journal of Virus Eradication, and many of the slide presentations are posted to the Forum website. READ MORE

Mosaic Antigens and Mountaineering Metaphors: Climbing Toward the Next HIV Vaccine Efficacy Trial
8/25/17 - The pharmaceutical industry has made significant contributions to HIV vaccine research, but it has been rare for a major company to take the leading role in propelling a candidate toward efficacy testing. The only example to date occurred around the turn of the millennium with Merck’s adenovirus serotype 5 (Ad5) vector, which showed some evidence of promise in macaque models but was ultimately discontinued after being associated with an enhanced—rather than reduced—risk of HIV acquisition in the STEP and Phambili trials. READ MORE

HIV Remission News from IAS 2017
7/25/17 - The 9th International AIDS Society Conference on HIV Science (IAS 2017) began on Sunday in Paris, and the topic of HIV remission has been the focus of several high profile presentations. READ MORE

Evidence of Smaller HIV Reservoirs in a Ugandan Cohort
6/12/17 - The size of the reservoir of replication-competent HIV that persists in individuals on ART has been described in several studies from North America, but no information has previously been presented from the African continent, where the burden of HIV infection is greatest. A study just published in Clinical Infectious Diseases by Jessica Prodger and colleagues takes a first step toward filling this gap, and the results may be surprising. READ MORE

Flagging the HIV Reservoir
3/16/17 - The rarity of CD4 T cells containing latent HIV in people on antiretroviral therapy—the typical estimate is around one per million CD4 T cells—makes them extremely challenging both to study and target with therapies. A paper published online yesterday in Nature represents a possible breakthrough in this area, reporting that it may be possible to identify many latently infected CD4 T cells due to expression of a particular cell surface protein, CD32a. READ MORE

Capsules From CROI 2017
3/10/17 - The annual Conference on Retroviruses & Opportunistic Infections (CROI) took place in Seattle from February 13th-16th, offering a dizzying parade of new data. Webcasts of presentations and PDF files of posters were rapidly placed online and are accessible via the CROI website. READ MORE

Targeting Latently Infected Cells via IFITM1
1/23/17 - One of the holy grails in cure research is the discovery of markers that would allow the specific targeting of cells harboring latent HIV. The goal is to be able flag those cells for elimination while sparing their uninfected counterparts. So far, a number of cellular receptors have been identified as being more commonly—but not exclusively— expressed on latently infected cells, such as PD-1, LAG-3 and TIGIT. In the new issue of the open access journal JCI Insight, Rui André Saraiva Raposo and colleagues from the laboratory of Doug Nixon at The George Washington University add a new candidate to the mix: interferon-induced transmembrane protein 1 (IFITM1). READ MORE

Therapeutic Vaccination Plus Toll-Like Receptor Stimulation Shows Promise in the SIV Model
12/16/16 - Since the earliest days of HIV research, the idea of trying to enhance immune responses to the virus using therapeutic vaccination has been extensively explored, but with little success. The ability of the virus to compromise CD4 T cells, which would normally coordinate antiviral immunity, may be one contributor to the generally disappointing results. Virus-induced damage to the lymph node environment where immune responses are initiated has also been suggested to play a role. Researchers have not given up, however, and a recent study in SIV-infected macaques has produced encouraging results. READ MORE

Applying the Brakes to Type 1 Interferons in HIV Infection
12/15/16 - This week in the Journal of Clinical Investigation, two independent studies describe results obtained by blocking type 1 interferon signaling pathways in humanized mouse models of chronic HIV infection. The papers are both open access (see Anjie Zhen et al and Liang Cheng et al). Type 1 interferons are cytokines that interact with specific receptors on cells in order to modulate activity of interferon-stimulated genes (ISGs), and these interactions are known to play important roles in antiviral immunity (e.g. alpha interferon is an approved treatment for hepatitis C). But the effects of type 1 interferons are complex, and can also involve potentially harmful exacerbation of immune activation and inflammation. In these new studies, the researchers used antibodies to block interferon receptors in humanized mice with chronic HIV infection, and converged on congruent findings: HIV viral loads and virus reservoirs were diminished, as were markers of immune activation and exhaustion. READ MORE

NIAID Strategies for an HIV Cure Workshop
11/11/16 - Next week from Monday through Wednesday the National Institute of Allergy and Infectious Diseases (NIAID) is convening their third scientific workshop on HIV cure research, Strategies for an HIV Cure 2016. The meeting will be held in the Ruth Kirschstein Auditorium at the Natcher Conference Center (Building 45) on the National Institutes of Health Main Campus. For the first time, the proceedings will be available for public viewing via live webcast at: A detailed agenda is available online. A room has been made available for the use of community advocates attending the workshop in person: Natcher room G1/G2 on the lower level of the conference center. 

Antibody Therapy Leads to Sustained Post-Treatment SIV Control in Macaques
10/17/16 - A study published last Thursday in the journal Science has hit the headlines, reporting that sustained post-treatment control of SIV has been achieved in macaques using an antibody therapy developed for the treatment of inflammatory gastrointestinal (GI) disorders. The antibody targets α4β7, a receptor expressed on CD4 T cells (and other immune system cells) that is involved in promoting trafficking to the GI tract. Some, but not all, studies have suggested that α4β7 also plays a role in mediating HIV infection of target CD4 T cells. READ MORE

HIV Persistence: Defective Virus Copies Accumulate Rapidly After Infection
9/14/16 - A major challenge in measuring the reservoir of HIV that persists despite antiretroviral therapy (ART) is that many of the virus genomes that can be found integrated into the DNA of CD4 T cells are incomplete or mutated in ways that preclude further rounds of replication. For researchers aiming to develop a cure, it is important to try and distinguish between defective virus copies and intact viruses capable of rekindling the infection when ART is interrupted. A new study from the laboratory of Robert Siliciano, published in the latest issue of Nature Medicine, attempts to assess the proportions of defective and replication competent HIV in people on ART, comparing individuals who began treatment very early after infection to those who started later. READ MORE

Probiotic-Based Vaccine Candidate Fails in Independent Study
5/20/16 - Back in 2012, a paper describing a study of a novel vaccine approach in the SIV/macaque model was published to little fanfare in the open access journal Cell Reports. The brainchild of researcher Jean-Marie Andrieu, the idea behind the vaccine was to turn the traditional approach to immunization on its head: the aim was to suppress the response to SIV, thereby depriving the virus of the activated CD4 T cell targets that normally fuel viral replication. A probiotic, Lactobacillus plantarum, was used to deliver SIV antigens to the gut with the goal of inducing SIV-specific immune tolerance. Macaques were then challenged with pathogenic SIV. The results were surprising and unprecedented: 15 out of 16 animals resisted infection. Protection was associated with the induction of SIV-specific CD8 T cells displaying a regulatory, immune-suppressive phenotype. READ MORE

Long-Awaited HIV Vaccine Efficacy Trial Gets the Green Light
5/18/16 - In 2009, a slight but statistically significant level of protective efficacy was reported from a large HIV vaccine trial conducted in Thailand. The trial, named RV144, involved a combination of an ALVAC canarypox vector encoding HIV antigens and a gp120 protein boost (AIDSVAX). Receipt of the vaccines was associated with a 31.2% reduction in the risk of HIV acquisition in a community sample of 16,402 adults aged between 18 and 30; the results were published in the New England Journal of Medicine. Ever since that time, plans have been afoot to assess whether the results can be duplicated or improved upon in other settings, and today the National Institute of Allergy and Infectious Diseases (NIAID) announced that a new efficacy trial is going to be launched in South Africa later this year. READ MORE

Snipping the HIV Genome Out of Latently Infected Cells
3/23/16 - One of the more futuristic-sounding ideas for curing HIV infection involves trying to remove the genome of the virus from the genome of the cells into which it has integrated. On paper, the idea is very appealing, but there are a multitude of challenges associated with trying to identify integrated HIV DNA (referred to as proviral DNA or provirus) and then excise it from the DNA of an infected cell without causing untoward effects. In 2014, the research group of Kamel Khalili at Temple University in Philadelphia drew extensive news coverage when they reported some success in laboratory experiments; this work and the media response were covered at the time on TAG’s media monitor page. Khalili and colleagues have now published a new paper and again have generated considerable press (in broad terms, TAG’s previous commentary on interpreting the research and associated stories remains relevant). In addition to Khalili’s new findings, another paper has been published recently that describes a slightly different approach toward excising HIV DNA, also reporting encouraging results but similarly limited to the laboratory setting. READ MORE

Cure Research News from CROI 2016
3/10/16 - The 2016 Conference on Retroviruses and Opportunistic Infections (CROI) took place in Boston from February 22-25. CROI deserves kudos for pioneering comprehensive webcasting, and all sessions are available for viewing online. Results from several significant cure-related clinical trials were debuted during the meeting (links to the webcasts are in parentheses): READ MORE

New Paper Rekindles Debate on HIV Replication During ART
2/4/16 - For many years scientists have probed the question of whether combination antiretroviral therapy (ART) completely inhibits all HIV replication in the body. The preponderance of evidence has suggested that it does, and opinion has generally tilted toward the idea that persistent virus replication in the face of ART is relatively uncommon. The evidence includes studies of ART intensification (adding multiple drugs to standard combinations), which in most—but not all—cases have documented no effect on levels of residual HIV, as well as genetic studies showing a lack of viral evolution over time in people on long-term treatment. The question remains controversial, however, and some scientists continue to believe that low-level ongoing HIV replication on ART may occur in hard-to-access sites in the body. READ MORE

HIV Cure Research Reviews in the Journal of Clinical Investigation
2/4/16 - The Journal of Clinical Investigation has published a collection of reviews on HIV cure research edited by Robert Siliciano. The articles are not open access unfortunately, but a day pass for the journal’s website (which allows downloading of all PDFs) costs $10 which is relatively affordable compared to many other publishers. READ MORE

New Data on the Latency-Reversing Activity of Disulfiram
12/1/15 - Several years ago, the laboratory of Robert Siliciano at Johns Hopkins University reported that the FDA-approved drug disulfiram (Antabuse) could reverse HIV latency in laboratory experiments. The discovery led Steve Deeks and colleagues to conduct a small pilot study in HIV-positive people on ART, which found that a standard dose of 500mg/day of disulfiram showed some hints of latency-reversing activity that appeared to be linked to whether drug levels were detectable in blood. In turn, the pilot study spurred the launch of a larger clinical trial investigating the effects of higher disulfiram doses (up to 2000mg/day) in a cohort of 30 HIV-positive individuals on ART. Results from this trial have now been published in The Lancet HIV. READ MORE

Developing Multi-Pronged Antibodies to Target the HIV Reservoir
11/11/15 - In an example of publication kismet, three recent open access articles all converge in describing a new strategy for depleting the HIV reservoir. The research involves engineering antibodies or antibody-like molecules capable of simultaneously binding two targets: the CD3 receptor, a human protein expressed on T cells, and parts of the HIV envelope (Env) protein, which are typically displayed on the outside of infected CD4 T cells when the virus is active. The rationale is that the region of the antibody that targets HIV Env binds to infected cells, while the CD3-targeting region binds to passing T cells and activates them to kill the cell. The idea for this two-pronged—termed bispecific—antibody attack originated in cancer research, and one candidate that targets CD19 (a protein expressed by B cells) and CD3 is already FDA-approved as a second-line treatment for certain forms of acute lymphoblastic leukemia. READ MORE

T-Cell Exhaustion Biomarkers Linked to Time to Viral Load Rebound in the SPARTAC Trial
11/11/15 - A study published in Nature Communications has drawn a fair amount of press coverage—and some hyperbolic headlines—by reporting that certain immunological biomarkers may be able to predict the likelihood of maintaining a low viral load after an antiretroviral therapy (ART) interruption. READ MORE

A Trio of Papers Provide New Insights Into Host Cell Manipulation by HIV
10/6/15 - Viruses are notorious for manipulating host cells in ways that favor viral replication, and HIV is no exception. The HIV protein Nef has a well-described capacity to subvert normal cellular biology, including down-regulating cell surface class I HLA molecules that might otherwise allow CD8 T cells to recognize that the cell is infected. Last week saw the publication of three independent studies that all report the discovery of another important Nef function. READ MORE

SMAC Mimetics and HIV Latency
10/6/15 - SMAC (Second Mitochondrial-derived Activator of Caspases) mimetics are a class of compounds that have recently entered clinical trials as potential cancer treatments. The drugs antagonize anti-apoptotic proteins, thereby promoting the apoptotic death of cancer cells. Earlier this year at CROI, a poster presentation offered evidence that SMAC mimetics may also selectively promote the apoptosis of CD4 T cells latently infected by HIV. In a new open access paper published by Cell Host & Microbe, Lars Pache and colleagues add another string to SMAC mimetics bow, reporting that the drugs can work synergistically with HDAC inhibitors to reverse HIV latency. In an experiment using resting CD4 T cells sampled from individuals on suppressive ART, the combination of the SMAC mimetic SBI-0637142 and the HDAC inhibitor panobinostat activated latent HIV as efficiently as T cell activation. Preliminary results from a phase I cancer trial suggest that the SMAC mimetic birinapant has an acceptable toxicity profile for testing in humans, potentially opening the door for studies of these compounds in HIV. READ MORE

Attempt to Oversell New Findings on Pyroptosis in HIV Infection Prompts Headline Debacle
8/28/15 - A new open access paper from the laboratory of Warner Greene at the Gladstone Institutes was published online yesterday in the journal Cell Reports, accompanied by a poorly conceived press release that prompted some of the most egregiously inaccurate media headlines about HIV research in recent history. READ MORE

Combining PKC Agonists and Bromodomain Inhibitors to Reverse HIV Latency
8/14/15 - Two recent papers in PLoS Pathogens report that combinations of candidate latency-reversing agents can potently activate HIV production by latently infected CD4 T cells in laboratory experiments. Pairings of the PKC agonists Bryostatin-1 or ingenol with the bromodomain inhibitor JQ1 were most effective, generating levels of virus production by latently infected cells similar to those achieved by maximal T cell activation. The results appear consistent with those published earlier this year by the research group of Robert Siliciano at Johns Hopkins University, and are encouraging because there had been some skepticism as to whether any latency reversing strategy could match the effects of maximal T cell activation (which is known to be too dangerous to use in people). But there are caveats: the compounds do affect T cell activation pathways and it is not yet known if they will be safe in HIV-positive individuals; currently, they are being tested (and in the case of ingenol, used topically) as cancer treatments. READ MORE

Estimating How Frequently Latent HIV Reactivates
8/7/15 - The primary barrier to curing HIV infection is the persistence of the virus in a latent form in long-lived resting memory CD4 T cells. The number of latently infected resting memory CD4 T cells in a typical individual on ART is estimated to be in the range of 1-60 million. An important strand of HIV cure research involves attempting to reduce the size of this persistent HIV reservoir, in hopes of delaying or—better yet—preventing viral load rebound when ART is interrupted. In order to gain insight into how feasible this might be, researchers have employed mathematical modeling to estimate how the size of the HIV reservoir relates to time to viral load rebound. READ MORE

Innate Immunity and HIV DNA Declines in Panobinostat Recipients
8/4/15 - Results from a phase I trial of the candidate latency reversing agent panobinostat were published last year in The Lancet HIV (see blog post from November 2014). The paper notes that in an exploratory analysis, a subset of four (out of a total of 15) participants experienced a significant decline in cell-associated HIV DNA levels of around 70-80%, although there was no detectable change in the trial cohort overall. Furthermore, the HIV DNA reduction in these four individuals was associated with a slightly longer time to viral load rebound during an analytical ART interruption. At the NIAID-sponsored Strategies for an HIV Cure meeting in October 2014, Matthias Lichterfeld reported that several measures of innate immunity correlated with the observed diminution of HIV DNA, and these analyses have now been published online in the Journal of Virology. READ MORE

News and Notes from IAS 2015
7/31/15 - Last week saw a slew of news emerge from the IAS 2015 conference and related satellite meetings in Vancouver. Below are links to some presentations of possible interest and information on how to find materials online. READ MORE

New Case of “Remission” Reported in a Perinatally Infected Teenager
7/23/15 - A new example of long-term post-treatment control of HIV viral load was reported on Monday at the 8th IAS Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2015) in Vancouver, attracting widespread media attention. Presented by Asier Sáez-Cirión from Institut Pasteur in France, the case involves a teenager who acquired HIV infection perinatally and was taken off ART at around the age of six, subsequently maintaining very strict control of viral load for over 12 years and counting. Sáez-Cirión is also the lead investigator for the well publicized VISCONTI cohort, a group of early-treated adults who are exhibiting long-term of HIV viral load after ART interruption (described in some detail in a paper in 2013, at which time the cohort had 14 members, and recently reported to now number 20 with an average time off ART of over nine years. Update 7/25/15: this information on the VISCONTI cohort appears to no longer be true, see addendum below). ). READ MORE

Interleukin-21 May Have Therapeutic Potential in HIV Infection
7/15/15 - Cytokines are a family of proteins that play important roles in immune cell communication. The best-known example is interleukin-2 (IL-2), which is FDA-approved as a therapy for kidney cancer. Many cytokines have been evaluated in HIV infection and one of the latest candidates being considered for human testing is IL-21. Laboratory and animal model research indicates IL-21 can enhance natural killer cell and CD8 T cell activity, and clinical trials are already underway in people with cancers. READ MORE

Prime-Boost HIV Vaccine Approach Shows Promise in Macaques; Janssen Aims to Advance to Human Efficacy Trials
7/14/15 - A paper published earlier this month in Science augurs a major new effort to advance a prime-boost HIV vaccine strategy into human efficacy trials. The vaccine components are manufactured by Crucell Holland B.V, which is now one of the Janssen Pharmaceutical Companies of Johnson & Johnson, and—in a very welcome development for the HIV vaccine field—Janssen has recently outlined a comprehensive development plan that they hope will lead to a licensable HIV vaccine. Frank Tomaka, MD, Clinical Leader, HIV Vaccines presented details on an AVAC webinar held May 18th (slides and audio are available online). Since the failure of Merck’s candidate in 2007, there has been a dearth of major pharmaceutical company involvement in HIV vaccine research, and planning for further efficacy trials was limited to one collaborative endeavor known as the Pox-Protein Public-Private Partnership (P5) (the work of P5 is also described on the AVAC webinar by Glenda Gray). The promising macaque results described in the new Science paper offer some insight into why Janssen has now entered the fray. READ MORE

Perspectives on Post-Treatment Control of HIV
5/22/15 - Several recent papers offer perspectives on the possibility of achieving post-treatment control of HIV replication by starting antiretroviral therapy (ART) during acute infection. Interest in this topic has been sharpened by reports about the VISCONTI cohort, a group of individuals in France who all started ART soon after HIV acquisition, maintained treatment for several years, then interrupted and are now controlling viral load to very low or undetectable levels. At the time of the last published update, the VISCONTI cohort included 20 individuals (identified from various trials) who have been off ART for an average of nine years. READ MORE

Enlisting Mice in the Search for Residual HIV
5/4/15 - One of the challenges in HIV cure research is developing methods for finding extremely low levels of replication-competent virus. For example, there have been three cases where individuals were considered possibly cured of HIV because the virus could not be detected even though ART had been stopped (the Mississippi baby and two Boston patients), but all ultimately experienced viral load rebounds. The research group of Joel Blankson at Johns Hopkins University is working on an approach to this problem involving mice, and recently published preliminary results in the Journal of Infectious Diseases. READ MORE

Mapping the HIV Integration Landscape: “Cancer Genes” and the Persistence of the Latent Reservoir
4/24/15 - Several presentations at last year’s CROI offered evidence that the proliferation and persistence of latently infected CD4 T cells is associated with HIV integration into certain genes that have also been implicated in the development of cancers. The results prompted the investigators to hypothesize that HIV integration into cancer-associated genes plays a causative role in sustaining the reservoir of latently infected CD4 T cells by promoting their survival. Some of the scientists involved in the research went so far as to suggest that the findings might somehow contribute to explaining the elevated risk of cancer in HIV-positive people (see the CROI 2014 summary on the blog). The studies were eventually published in Science last July, along with a commentary by David Margolis and Frederic Bushman pointing out that “most HIV-related malignancies are not T cell cancers, and even most HIV-related lymphomas are of B cell origin” and gently noting: “alternative interpretations of the data are possible." READ MORE

Combining Latency-Reversing Agents, and Reviewing Methods of Measuring the Latent HIV Reservoir
4/16/15 - At CROI last year, Gregory Laird presented results from a laboratory study that tested the activity of several candidate HIV latency-reversing agents (LRAs) on latently infected CD4 T cells isolated from HIV-positive individuals on ART. The results were disappointing: only one LRA showed a very modest effect on HIV gene expression and none induced significant production of HIV virions (the study was later published in Nature Medicine). Laird concluded his CROI talk by offering a glimpse at more hopeful preliminary data suggesting that combinations of LRAs could perform better, and these experiments have since been completed and were published recently in the Journal of Clinical Investigation (the paper is open access). READ MORE

Broadly Neutralizing Antibody Suppresses HIV in Clinical Trial
4/9/15 - The past decade has seen a boom in the identification of antibodies capable of potently neutralizing a broad array of different HIV isolates (broadly neutralizing antibodies or bNAbs). New technologies that allow antibodies to be fished from huge numbers of individual B cells and tested for activity have spurred this rapid acceleration of discovery. There is now intense interest in learning whether the blossoming array of bNAbs can be put to therapeutic and preventive use. A paper published yesterday in Nature describes encouraging results from a phase I trial involving the bNAb 3BNC117. Reflecting the level of interest in the topic, the paper has attracted extensive press coverage. READ MORE

Souped-Up IL-15 Sparks Natural Killer Cell Activity Against HIV
4/9/15 - The cytokine interleukin-15 (IL-15) can exert a range of effects on the immune system, but is particularly important for promoting the proliferation and function of natural killer (NK) cells and CD8 T cells. Some observational studies in HIV have suggested salutary effects of higher IL-15 levels, in one case finding an association with delayed viral load rebound after ART interruption. But attempts at therapeutic administration of the cytokine to SIV-infected macaques have generally produced deleterious effects, including CD4 T cell depletion. More recently, IL-15 has been reexamined in the context of cure research, with laboratory studies demonstrating it can induce latently infected CD4 T cells to produce HIV. There is also increasing interest in therapeutic manipulation of NK cell responses as a means to eliminate the HIV reservoir, a task for which IL-15 may be well suited. A paper published last week in the Journal of Virology reports that an optimized form of IL-15 promoted potent inhibition of HIV by NK cells in humanized mice. READ MORE

CROI 2015 Round Up
3/18/15 - The 2015 Conference on Retroviruses and Opportunistic Infections (CROI) took place in Seattle from February 23rd to the 26th. The major news that emerged from the meeting was the extremely high degree of protection from HIV infection obtained with pre-exposure prophylaxis in two studies, PROUD and IPERGAY. On the vaccine and cure fronts nothing was quite as headline grabbing, but there were a number of interesting presentations. Webcasts of all conference sessions are available on the CROI website along with the abstract book and, where available, PDFs of posters. Excellent coverage of CROI is available from several websites, including AIDSMap, i-Base and NATAP (whose reports often include slides from the talks). READ MORE

Novel, Broadly Active HIV Inhibitor Shows Potential
2/19/15 - A paper published yesterday in Nature has stirred considerable excitement and widespread media coverage. Led by the laboratory of Michael Farzan at The Scripps Research Institute, the research involves a newly designed inhibitor of HIV named eCD4-Ig. The inhibitor is designed to bind the HIV envelope at sites that attach to CD4 and CCR5 molecules on CD4 T cells; blocking this interaction prevents HIV from gaining entry and infecting the cell. In laboratory experiments, eCD4-Ig showed activity against an unprecedentedly broad array of HIV and SIV variants, including viruses known to be resistant to even potent neutralizing antibodies. In addition to the greater breadth, activity was generally achieved at lower concentrations than has been documented with the broadly neutralizing antibodies (bNAbs) described to date. Due to similarities between HIV envelope binding to CCR5 and CXCR4 co-receptors, eCD4-Ig also proved capable of neutralizing CXCR4-dependent virus isolates. These results prompted the researchers to explore the preventive potential of eCD4-Ig in the rhesus macaque model, and it is the outcome of this part of the study that has particularly spurred the publicity. READ MORE

Report of “Aggressive” HIV Variant in Cuba
2/18/15 - On January 28th, a paper reporting evidence of rapid progression associated with a recently identified HIV-1 recombinant circulating in Cuba (CRF19_cpx) was published online by the journal EBioMedicine. CRF stands for circulating recombinant form, and CRF19_cpx represents a combination of HIV-1 subtypes A, D and G. Last week, the authors issued a press release about the study, and since then media coverage has gradually ballooned. Most of the coverage takes its lead from the press release headline: “An aggressive form of HIV uncovered in Cuba.” The immediate problem is that the data are very preliminary, and it is way too soon to declare—as fact—that what has been uncovered is “an aggressive form of HIV.” It may or may not be, additional evidence is needed in order to make that determination. Many media stories also state that HIV CRF19_cpx causes AIDS within three years, which is potentially very misleading because what the study reports is that this rapid pace of progression occurred in a total of nine untreated people who were found to be infected with the strain; this does not prove that all people infected with HIV CRF19_cpx will progress at this rate. There is no evidence to suggest that HIV CRF19_cpx would not respond to treatment. READ MORE

Lymphoid Tissue Fibrosis: New Studies and Candidate Therapies
1/30/15 - Research has documented that HIV infection is associated with significantly increased scarring damage to lymphoid tissue, termed fibrosis. Fibrosis can be quantified by measuring the deposition of collagen, and the amount of lymphoid tissue fibrosis in HIV-positive people has been shown to correlate directly with CD4 T cell depletion. A paper published toward the end of last year by Timothy Schacker’s group at the University of Minnesota describes results of an analysis of gut-associated lymphoid tissue (GALT) fibrosis in untreated HIV controllers and HIV-positive people on ART, compared to HIV-negative controls and the one person considered cured of HIV, Timothy Brown. The study was previously presented in part at CROI 2013. READ MORE

Latency-Reversing and Immunomodulatory Activities of HDAC Inhibitors
12/5/14 - Results from the second clinical trial to test the HDAC inhibitor vorinostat as a latency-reversing agent, first presented at CROI 2013, have now been published in the open access journal PLoS Pathogens. The study design differed from the first trial, involving a longer 14-day dosing period. The results are broadly consistent, with a significant increase in cell-associated HIV RNA documented, but no change in multiple measures of the HIV reservoir or HIV RNA as assessed by the standard viral load test. Side effects experienced by participants were grade 1 or 2 (mild or moderate in severity) with lethargy, diarrhea and thrombocytopenia being most common; all resolved after the drug was stopped. The researchers noted long-term changes in expression of multiple cellular genes and caution that this could present a safety concern, stating: “the prolonged changes in host gene expression require careful long term follow up.” READ MORE

Is HIV Weakening Over Time?
12/2/14 - A little over nine years ago I wrote a blog post with this same title, about a widely publicized paper claiming that HIV had become less virulent. Although it's grim to be in the position of pouring cold water on optimistic-sounding scenarios, that paper was based on measuring HIV’s ability to replicate using a laboratory test, and other published data raised questions as to whether the test could actually predict differences in disease progression rates. Today, it’s déjà vu all over again because there has been an explosion of very similar media stories positing that HIV is evolving into a “milder form." And once again, the study prompting the coverage relies primarily on laboratory measurements of HIV replication capacity, despite the fact that a prior publication—by several of the same authors—reports that results from this test do not predict the rate of CD4 T cell decline over time. READ MORE

TAG HIV Cure Research Media Monitor
11/26/14 - In recent months, Treatment Action Group has created a web page resource that will attempt to provide accurate information on HIV cure research news that makes a splash in the mainstream media, particularly those stories that get mangled in the translation or are possibly based on dubious scientific claims. READ MORE

Update on Early HIV Treatment in Infants: IMPAACT Trial Launched, Additional Case Reports Published
11/26/14 - On November 3rd, the National Institute of Allergy and Infectious Diseases (NIAID) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) announced the launch of the IMPAACT P1115 trial, which will investigate very early initiation of HIV treatment in newborns. Much of the impetus for the trial came from the Mississippi baby case, and although that has turned out to involve an extended, 27-month remission from HIV replication rather than a cure, there remains a rationale for evaluating the feasibility, benefits and risks of early treatment in perinatal HIV infection. READ MORE

Three Papers on Macrophages and HIV Infection
11/25/14 - The question of whether HIV infection of macrophages plays an important role in pathogenesis remains controversial and unresolved. For cure researchers, the related question of whether macrophages contribute to viral persistence during antiretroviral therapy is crucial, but also unanswered. Three recent papers describe results from studies designed to shed light on this subject. READ MORE

HIV Reservoir Measurements and Viral Load Rebound after ART Interruption
11/18/14 - To assist in the search for therapies that might contribute to curing HIV infection, scientists are seeking to identify biomarkers that are associated with control of viral load after an antiretroviral therapy (ART) interruption. If reliable predictors of viral load control could be identified, the effect of candidate therapies on these biomarkers could be evaluated without necessarily having to ask clinical trial participants to undergo ART interruptions (which can pose risks to health). Two recent papers report that certain measurements of the HIV reservoir show statistically significant associations with viral load rebound, although the results are not entirely consistent. READ MORE

Panobinostat as a Latency-Reversing Agent: Phase I Trial Results Published
11/6/14 - In the spring of 2013, a wildly inaccurate Daily Telegraph story about HIV cure research claiming “there will be a breakthrough in finding a cure for HIV within months” was amplified around the Internet, understandably receiving a massive amount of attention and interest. To their credit, the researchers whose work prompted the piece published a statement addressing the inaccuracies, and eventually the Telegraph made extensive corrections. Recently, in the debut issue of The Lancet’s new online HIV journal, results from the trial at the center of the story were published - to no fanfare whatsoever. READ MORE

9/3/14 - Two recent papers address the potential of broadly neutralizing antibodies (bNAbs) to decrease HIV rebound from persistent reservoirs. In the journal Cell, Ariel Halper-Stromberg and colleagues report the results of experiments conducted in the humanized mouse model with a “tri-mix” of three monoclonal bNAbs: 3BNC117, 10-1074, and PG16. When administered as post-exposure prophylaxis four days after the mice were challenged with HIV, the bNAb tri-mix did not prevent infection, but there was a significant delay in viral load rebound after the treatment was stopped (compared to a control group of mice given combination antiretroviral therapy on the same schedule). The researchers conclude that the bNAbs were more effective than ART at preventing the formation of the latent HIV reservoir in the mice, likely due to antibody-mediated effector mechanisms facilitating the clearance of infected cells (similar to recent findings in the macaque model). READ MORE
8/28/14 - A letter published yesterday in the New England Journal of Medicine describes the outcome of a recent attempt to repeat the HIV cure achieved in Timothy Brown. An HIV-positive individual requiring stem cell transplantation for the treatment of cancer (anaplastic large-cell lymphoma) was matched with a donor homozygous for the CCR5Δ32 mutation, which renders cells resistant to CCR5-tropic HIV.  Pre-transplant analyses indicated that the majority of HIV in the individual was CCR5-tropic, but there was also evidence of HIV strains capable of entering cells via the CXCR4 (X4) receptor. READ MORE
8/26/14 - Several independent research groups have identified ingenol esters, compounds derived from the tropical shrub Euphorbia tirucalli, as potent activators of latent HIV. Papers published in the journals Virology and AIDS report that a specific semi-synthetic ingenol ester named 3-caproyl-ingenol (ING B) demonstrates the greatest promise and may represent a candidate for clinical trials. The compound appears to work by targeting the protein kinase C (PKC) pathway, similar to another known latency-reversing candidate prostratin but with less evidence of toxicity. At the International Workshop on HIV Persistence last December, Lucio Gama from Johns Hopkins University presented results from ING B studies in SIV-infected macaques indicating that the drug was safe to administer and showed activity against latent virus. Gama also offered a glimpse at preliminary data from the laboratory of Robert Siliciano suggesting that ING B potently activated latent HIV in CD4 T cells isolated from HIV-positive individuals on ART. Additional analyses are ongoing with a view to assessing if ING B can safely be advanced into human clinical trials, and whether additional modifications to the compound might enhance safety and activity. READ MORE
7/16/14 - The 20th International AIDS Conference (AIDS 2014) begins Sunday in Melbourne. A number of sessions and potentially interesting abstracts cover HIV cure research, and a two-day International AIDS Society (IAS) symposium on the topic immediately precedes the main meeting on July 19th and 20th (the program for the symposium is available online). Recommendations for some relevant sessions and abstracts are below, there is also an official IAS “Towards an HIV Cure” conference roadmap on the AIDS 2014 website. READ MORE
7/16/14 - Initial results from the Canadian pediatric HIV research mentioned in a recent blog post were published in Clinical Infectious Diseases on June 9th. The paper notes that Canada’s three pediatric HIV care institutions have a longstanding policy of administering triple drug antiretroviral therapy (ART) regimens to newborns considered at a high risk of HIV infection (either because the mother has detectable viral load at delivery or, in the absence of viral load results, if there is evidence of non-adherence to ART). Treatment is continued if HIV infection is subsequently confirmed. The researchers, inspired in part by the Mississippi baby case report (before the news of viral rebound emerged), searched their records for examples of children who had been started on ART within 72 hours of birth. A total of 136 were identified and, of those, 12 were confirmed to have acquired HIV infection. Four have since been maintained on ART with continuous viral load suppression; ages range from 2.5-7.5 years. READ MORE
7/11/14 - Understandably, there has been extensive media coverage of yesterday’s announcement that HIV has rebounded in the “Mississippi Baby” case. Although a full discussion of the implications will take time, there are some points that I think may be worth noting now: READ MORE
7/10/14 - On June 17th, the Forum for Collaborative HIV Research convened a meeting in Washington DC to discuss regulatory issues relating to HIV cure research. Youtube videos of all the sessions, slide presentations and associated meeting materials (including an Excel file with detailed cure research trial information) are now available on the Forum’s HIV Cure Project webpage. A paper summarizing the outcomes from meeting will be forthcoming.
7/10/14 - A news release issued today by the National Institute of Allergy and Infectious Diseases (NIAID) reports the disappointing news that viral load has rebounded in the child in Mississippi who had been considered possibly cured of HIV infection. The child is now nearly four years of age and HIV had remained undetectable without treatment for over two years, but recent routine laboratory testing revealed a viral load of 16,750 copies that was confirmed 72 hours later with a second measurement of 10,564 copies. HIV-specific antibodies are also now detectable and CD4 T cell numbers have declined. The child has been restarted on antiretroviral therapy and is said to be responding well. Genetic sequencing was used to establish that the rebounding HIV was derived from the virus present in the mother. READ MORE
6/6/14 - An open access paper published in the Journal of Infectious Diseases reports that earlier HIV suppression by ART is associated with significantly smaller HIV reservoirs in perinatally infected youths. The study, by Katherine Luzuriaga and colleagues, was initially presented at CROI last year and compared two groups of four individuals: one group started ART at 0.5–2.6 months of age and the other at 6-14.7 years of age. HIV DNA levels were significantly lower in the early-treated group, and replication-competent virus could only be detected in one out of the four, at a very low level, but was found in all of the late-treated study participants. Additionally, there was evidence of a decrease in HIV DNA levels over time in the early-treated group. At this year’s CROI, Deborah Persaud described a similar but much larger analysis that echoed these findings, and also identified negative or indeterminate HIV antibody tests as a marker for smaller reservoirs (the presentation can be viewed via webcast). READ MORE
5/21/14 - Since posting recently about studies investigating the relevance of the CD4/CD8 ratio in the antiretroviral therapy era, several new papers and presentations have provided more information on the topic. Last week in the open access journal PLoS Pathogens, Sergio Serrano-Villar and colleagues reported evidence that a low CD4/CD8 ratio (less than or equal to 0.4)—despite CD4 T cell recovery to a count above 500 on ART—is associated with low naïve CD8 T cells, elevated levels of activated and senescent CD8 T cells, increased innate immune activation, and a greater risk of non-AIDS events. After controlling for age, gender, ART duration and both nadir and proximal CD4 count, each 10% decrease in the CD4/CD8 ratio was associated with 48% higher odds of serious non-AIDS events. In a separate cohort that started ART with advanced disease, a significant correlation between the CD4/CD8 ratio and the risk of mortality was documented. In this analysis, the researchers report that for each 10% increase in the CD4/CD8 ratio on ART there was a 15% decrease in the risk of death. Individuals initiating ART earlier in the course of HIV infection exhibited greater and more rapid improvements in the CD4/CD8 ratio compared to those starting late. READ MORE
5/16/14 - In addition to studies covered in prior posts (a possible second pediatric cure case, Sangamo’s gene therapy and limitations of latency-reversing agents), CROI 2014 featured a smorgasbord of presentations related to pathogenesis and cure research. Webcasts of all conference sessions are online, and many posters are now available in PDF format. Brief summaries of some notable studies are appended below, with links to webcasts and posters included where possible. Abstracts for posters that are unavailable as PDFs can be found in the final program and abstract book. READ MORE
4/10/14 - The persistence of a latent form of HIV integrated into the genome of long-lived cells, particularly memory CD4 T cells, is considered the most significant barrier to curing the infection. A key element of cure research is the pursuit of strategies capable of inducing latent HIV to replicate, with the aim of causing the death of the latently infected cell either as a result of viral cytopathic effects or recognition and elimination by HIV-specific immune responses (or other targeting strategies). A number of candidate latency-reversing agents (LRAs) have emerged from studies, with the anticancer drugs HDAC inhibitors leading the pack. Two clinical trials of the HDAC inhibitor vorinostat have indicated that it is capable of inducing latent HIV to begin making viral RNA, but whether subsequent steps in the viral life cycle ensued—the manufacture of HIV proteins and their assembly into infectious virions—is not yet known. Two recently published studies set out to better understand the capabilities of the current crop of LRAs, including HDAC inhibitors, and report that they may not be up to the task, at least as single agents. READ MORE
3/21/14 - Having recently criticized a widely publicized paper on HIV-induced pyroptosis for not providing much information relating to CCR5-tropic HIV infection, I’m duty bound to highlight a new study that includes some data addressing this topic. Pyroptosis is an inflammatory form of cellular suicide that has been shown by Gilad Doitsh from Warner Greene’s laboratory to result from abortive HIV infection of resting “bystander” CD4 T cells in lymphoid tissue, leading to a massive depletion of these cells. The effect is dramatic with CXCR4-tropic HIV isolates, because the majority of resting CD4 T cells express the CXCR4 receptor. In a paper published in Science earlier this year, Doitsh’s research group identified the human IFI16 protein as the sensor that detects HIV genetic material in these cells, leading to pyroptosis. Doitsh has also demonstrated that the phenomenon can be induced by CCR5-tropic HIV isolates in CCR5-expressing CD4 T cells, but because CCR5 is most commonly expressed on activated cells and is very rarely present on resting CD4 T cells, the number of bystander cells that might die as a result of pyroptosis in the setting of CCR5-tropic HIV infection is as yet unclear. The new study, published in Retrovirology by Amanda Steele and colleagues, reports evidence that pyroptosis occurs in gut CD4 T cells after exposure to CCR5-tropic HIV, despite the fact that most of these cells appear to be activated (and therefore potentially susceptible to productive, rather than just abortive, infection). READ MORE
3/18/14 - One of the less-discussed factors that influences susceptibility to HIV infection is immune activation, which is interlinked with the availability of potential target cells for the virus. Several recent papers and a poster presentation at CROI 2014 shed additional light on this topic. In an open access review published in Retrovirology last November, Catherine Card and colleagues provide an overview of the science, focusing particularly on data generated by their studies of HIV risk factors among female sex workers in the Pumwani district of Nairobi, Kenya. This work has identified lower levels of immune activation—described as immune quiescence—as protective against HIV acquisition, and implicated specific polymorphisms in the interferon regulatory factor 1 (IRF-1) gene as contributing to the phenomenon. The same research group also published a study in the Journal of Infectious Diseases in January reporting that long-term (>1 year) involvement in sex work is associated with reduced mucosal immune activation, perhaps as a result of chronic exposure to diverse foreign antigens inducing regulatory, tolerance-like immune mechanisms. Based on these observations, a trial is about to be launched in Nairobi that will evaluate if daily administration of aspirin or hydroxychlroroquine can reduce systemic and mucosal immune activation in HIV-negative women. READ MORE
3/17/14 - Recently there have been two widely publicized updates relating to SB728-T, a gene therapy for HIV infection developed by Sangamo BioSciences. On Wednesday March 5th the New England Journal of Medicine (NEJM) published results from a phase I study conducted by Pablo Tebas and colleagues at the University of Pennsylvania, and on the following day at CROI 2014 Gary Blick presented new data derived from subsequent trials. The therapy is technologically complex: it involves extracting CD4 T cells from HIV-positive individuals and then modifying them with a method that aims to disable the gene that encodes the CCR5 receptor (which most HIV variants use as a foothold to gain entry into cells). The CD4 T cells are then expanded in number and ultimately infused back into the individual, typically with around 10% successfully modified so that they no longer express CCR5. The method for disabling the CCR5 gene involves an enzyme called a zinc finger nuclease (ZFN), which targets and breaks the DNA containing the gene; cellular repair enzymes then stitch the DNA back together in a way that prevents the gene from making a functional CCR5 receptor. The ZFN is delivered into the CD4 T cells by an adenovirus vector during the laboratory modification procedure. The goal of the therapy is to create a population of CD4 T cells that are resistant to infection by HIV. READ MORE
3/6/14 - The 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014) opened in Boston on Monday and concludes today. The media is awash with stories relating to a conference presentation by Deborah Persaud from Johns Hopkins University, in which she described the case of an HIV-infected baby who was treated within four hours of birth and now shows no detectable HIV after nine months of follow up. The diagnosis of HIV infection was established by a positive HIV DNA test and detectable viral load measurements of 217 copies/mL in the blood (36 hours after birth) and 32 copies/mL in the cerebrospinal fluid (on day 6, sampled as part of a work up for meningitis). Crucially, the infant remains on antiretroviral therapy (ART) so it is as yet unknown if they have been cured. According to news stories, doctors may consider interrupting ART if tests continue to show an absence of detectable HIV when the child reaches two years of age. READ MORE
2/14/14 - Elite controller is a term applied to the rare group of HIV-positive individuals who maintain undetectable viral loads in the absence of any treatment. The precise criteria for defining elite controllers often varies from study to study, particularly when it comes to the duration of viral load control. A research group based in the UK has recently published two companion papers—a systematic review and a research study—that attempt to document the various definitions that have been used in the scientific literature and identify the most accurate using data from a large cohort of HIV-positive individuals. READ MORE
2/13/14 - In the late 1990s, a single case report about an individual displaying control of HIV viral load for nearly two years after interrupting antiretroviral therapy (ART) drew a huge amount of publicity, including a lengthy story in the New York Times magazine by Mark Schoofs in June of 1998. The case report was ultimately published in the New England Journal of Medicine on May 27, 1999. The man was dubbed “the Berlin patient” long before the moniker was also applied to Timothy Brown, the only adult considered cured of HIV infection. This first Berlin patient was under the care of Dr. Heiko Jessen, and he was treated with the unusual combination of ddI (Videx), indinavir (Crixivan) and the cancer drug hydroxyurea (which at the time was sometimes used both to potentiate ddI and for possible immune-modulating activity). Treatment was started during acute infection and subsequently interrupted twice for short periods before being completely discontinued. During the second interruption and after discontinuation, HIV viral load levels remained undetectable based on the assay in use, which had a cut-off of 500 copies/ml. The individual was reported to have strong HIV-specific CD4 T cell and CD8 T cell responses, suggesting cellular immunity might be responsible for the salutary outcome. READ MORE
2/11/14 - Over the past few years there has been growing interest in the use of adeno-associated virus (AAV) as a vehicle for generating anti-HIV neutralizing antibodies in humans. The approach is different from traditional vaccination, in that AAV is used essentially as a gene therapy: the AAV vector is designed to take up residence in cells and then act as a factory for churning out broadly neutralizing antibodies against HIV (genes that encode these antibodies are inserted into the vector). This novel idea may be able to circumvent the challenging problem of inducing the production of broadly neutralizing antibodies with traditional vaccines, and could potentially offer significant protection against HIV acquisition. READ MORE
2/6/14 - A subset of HIV-positive people who initiate antiretroviral therapy (ART) and achieve suppression of HIV replication experience poor recovery of CD4 T cell numbers. Terms used to describe this subset of individuals include “discordant responders” and “immunological non-responders” (INRs). As yet, there is no universally accepted definition of INRs and a variety of CD4 T cell thresholds are cited in the scientific literature (e.g. persistently below 200, 250 or 350 cells despite HIV suppression). Depending on the definition, estimates of the proportion of people starting ART who can be categorized as INRs are typically around 5-20%. In studies conducted to date, the most consistently reported risk factors for this outcome are low CD4 T cell counts at the time of ART initiation and older age. Several published studies have also reported that INRs have a greater risk of morbidity and mortality compared to HIV-positive individuals with more robust CD4 T cell gains. READ MORE
2/5/14 - An inversion of the normal ratio between CD4 and CD8 T cells was noted in the very first case reports of individuals with AIDS, before HIV was even identified. Although a number of studies subsequently reported an association between the CD4/CD8 ratio and risk of disease progression, CD4 T cell counts were more extensively researched and became the most commonly used surrogate marker of immune system health in HIV-positive people. In recent years, data has emerged from cohort studies of very elderly HIV-negative people indicating that, in this population, the CD4/CD8 ratio is a strong predictor of the risk of aging-associated diseases and mortality. This new information prompted the research group of Sergio Serrano-Villar at the University Hospital Ramón y Cajal in Madrid to evaluate whether measurement of the CD4/CD8 ratio may provide information about the risk of morbidity and mortality in HIV-positive people in the current era of antiretroviral therapy (ART). READ MORE
1/17/14 - At the IAS conference last July, Victor Garcia described results obtained in the humanized mouse model with a strategy that targets HIV-infected cells for elimination. The study was published in PLoS Pathogens last week, drawing considerable media coverage. The strategy involves the use of an “immunotoxin” – a combination of an antibody fragment that recognizes a relatively conserved part of the HIV-1 envelope protein and a cell-killing toxin derived from Pseudomonas bacteria. Prior studies have shown that the immunotoxin is capable of recognizing and killing HIV-infected cells in a lab dish. Garcia’s study demonstrated that the addition of the immunotoxin to antiretroviral therapy (ART) led to more extensive depletion of HIV-infected cells in multiple tissues in humanized mice compared to ART alone (over about two months of follow-up). READ MORE
1/15/14 - The increasing research focus on curing HIV infection has led to an admirable uptick in the number of large scale collaborative studies in which multiple scientific groups work together in order to advance the field. Last year saw the publication of one such study that compared approaches to measuring the HIV reservoir, highlighting the strengths and weaknesses of each technique. Now several independent laboratories have collaborated on a comparison of the different laboratory methods for measuring the effectiveness of compounds that aim to awaken latent HIV (believed to be a key step for eliminating the latent HIV reservoir in HIV-positive individuals on ART). These methods are important because they help researchers decide whether a compound is active enough to be studied in people. READ MORE
12/20/13 - Two new papers describing a recently discovered mechanism of CD4 T cell death in HIV infection are receiving extensive press coverage. Both are from the laboratory of Warner Greene at the Gladstone Institutes, and follow up on their prior work published in the journal Cell in 2010. The papers have simultaneously appeared in two high profile journals, Nature and Science, prompting the slew of publicity. Unfortunately, the media is largely failing to convey the subtleties and uncertainties associated with the research. The most common narrative being offered is that the cause of CD4 T cell depletion in HIV infection has remained a mystery, which the new studies have now solved. This is not just an oversimplification; it is not true. READ MORE
12/6/13 - In July of 2012, Timothy Henrich from Brigham and Women's Hospital in Massachusetts first reported on two HIV-positive individuals in the Boston area who had undergone stem cell transplants to treat cancers, and subsequently lost all detectable traces of virus reservoirs. These case reports were later published in the Journal of Infectious Diseases. Both individuals were maintained on antiretroviral therapy (ART) throughout the transplantation procedures and afterward, so initially it was uncertain if the results represented a profound depletion of HIV reservoir levels or a cure of the infection. Earlier this year Henrich presented short-term results after ART interruptions, drawing widespread attention because HIV levels remained undetectable (for seven and 15 weeks of follow up, respectively), prompting hope that a cure may have been achieved. But yesterday at a scientific conference in Miami, Henrich shared the disappointing news that HIV viral load has since rebounded to detectable levels in both individuals, leading to the restarting of ART—in one case in August of this year, in the other more recently after eight months off treatment. READ MORE
11/13/13 - Following up on the prior post about broadly neutralizing antibodies (bNAbs) against HIV, there is now a free database available ( that offers detailed information on all known bNAbs. The genesis and purpose of the database is described in an open access paper in the journal Nucleic Acids Research. Although not a focus of the paper, it's worth noting that the discovery of growing numbers of bNAbs has been facilitated by major investments in the research, particularly by National Institutes of Health funding for the Center for HIV/AIDS Vaccine Immunology and, more recently, two Centers for HIV/AIDS Vaccine Immunology & Immunogen Discovery (at Duke University and the Scripps Institute) and also by the non-profit International AIDS Vaccine Initiative (IAVI) though its Neutralizing Antibody Consortium. READ MORE
11/1/13 - HIV is notoriously stubborn in its ability to thwart attacks by antibodies. The sugary outer envelope of the virus is so effective in cloaking its vulnerabilities that, for many years, the number of antibodies known to have broad neutralizing activity against HIV could be counted on one hand. But recently, collaborative research efforts aiming to identify and isolate more broadly neutralizing antibodies (bNAbs) have paid extraordinary dividends, increasing the number well into double digits and discovering several bNAbs with significantly greater breadth and potency than ever seen before (each isolated antibody is assigned a name, e.g. VRC01, PGT121, etc.). Although the primary impetus for this work is the development of an effective preventive HIV vaccine, there is also interest in exploring whether infusions of these new bNAbs may have therapeutic potential. A study published last year in the journal Nature reported encouraging signs of efficacy in a humanized mouse model, and this past Wednesday two research teams reported similarly promising results in macaque monkeys, drawing considerable media attention. READ MORE
10/25/13 - At a symposium on cure research held prior to the International AIDS Conference in 2012, Robert Siliciano presented new data suggesting that the amount of replication-competent latent HIV that persists in the face of antiretroviral therapy (ART) may be greater than previously appreciated (the video and powerpoint from Siliciano’s talk are available on the symposium website). This research, led by Ya-Chi Ho from Siliciano’s laboratory at Johns Hopkins University, has now been published in the journal Cell. The paper expands on the originally reported findings, and concludes that the latent HIV reservoir may be at least 60-fold larger than prior estimates. READ MORE

Update on the Mississippi Infant Cure Case
10/24/13 - The widely publicized case report regarding an infant in Mississippi who may have been cured of HIV infection after receiving very early antiretroviral therapy (ART) has now been published in the New England Journal of Medicine. The case was presented at CROI earlier this year and covered in detail on this blog at that time. The paper is largely based on the previously presented data, but provides a brief update in the discussion section: the infant is now 36 months of age and remains in care, having now been off ART for at least 18 months without any return of HIV RNA (an additional 8 months of follow up from the prior report). The journal publication is accompanied by an editorial commentary from Scott Hammer. READ MORE

10/10/13 - A conference being held in San Francisco from November 3-5, named “What Will it Take to Achieve an AIDS-free World?” and sponsored by the scientific journals The Lancet and Cell, is ignominiously answering the question posed in the title of this post: don’t provide an option to register until less than a month before the event and charge a $400 registration fee (the public registration option at this “special rate” was only added to the conference website in the last couple of days). TAG’s plea to the organizers—made in March of this year—requesting that they at least allow an option for local community members to attend without paying a steep fee has seemingly fallen on deaf ears. It is lamentable that an event attempting to look toward a brighter future should harken back to the dark days when people with HIV and community-based activists were excluded from attending scientific meetings. Hopefully some of the esteemed speakers—which do at least include respected activist David Evans from Project Inform—will raise this issue in their talks.
9/26/13 - A study published on September 12th by the journal Immunity ties together two emerging areas of HIV vaccine research. In recent years, scientists have discovered that a small proportion of chronically infected individuals develop antibody responses capable of broadly neutralizing a diverse array HIV isolates. These antibody responses typically take years to develop, and are not present at sufficient titers to offer noticeable benefit to the infected individuals they are isolated from, but there is reason to believe that if they could be induced by a vaccine they could protect uninfected people against HIV acquisition. A potential complement to this line of investigation has been the discovery of T follicular helper cells (Tfh), a specialized CD4 T cell subset that plays a critical role in providing help to B cells, thereby facilitating antibody production. Researchers have posited that Tfh may have an important role in the generation of broadly neutralizing antibodies against HIV, but direct evidence has been lacking. READ MORE
7/16/13 - In April, doctors at the University of Minnesota announced that they were attempting to reproduce the cure achieved in Timothy Brown in a 12-year old boy with HIV and leukemia who required a stem cell transplant. Due to the challenges associated with identifying appropriate adult stem cell donors homozygous for CCR5Δ32 (as was done for Brown), the Minnesota team—led by Dr. John Wagner—obtained cord blood stem cells from the limited available supplies that have been screened for the mutation (the current status of screening efforts is described in a recent review article). Permission was obtained from the Food and Drug Administration (FDA) to conduct the procedure, and it was performed on April 23rd. READ MORE
7/16/13 - Vaccine vectors based on adenoviruses—which are common in nature and cause severe colds—were once viewed as promising for HIV and other intractable diseases due to their ability to induce antigen-specific CD8 T cell responses in the majority of recipients. The subsequent Icarus-like trajectory of the approach in HIV has been covered in some detail on this blog, starting with the results of the first efficacy trial of Merck’s now-discontinued adenovirus serotype 5 (Ad5) candidate (the Step study), which showed that the vaccine significantly increased the risk of HIV acquisition and did not significantly lower viral load or preserve CD4 T cell counts in participants who became infected. READ MORE
7/9/13 - The 7th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2013) took place from June 30-July 3 in Kuala Lumpur and featured a pre-conference symposium and several sessions on HIV cure research. Webcasts and powerpoints of at least some presentations are being made available on the conference website (see links below). READ MORE
5/10/13 - Last year Steven Yukl from UCSF presented the results of an exhaustive search for HIV genetic material in Timothy Brown (aka the Berlin Patient)—the one adult individual considered cured of the infection. The study engendered controversy, because a few of the multiple independent laboratories that participated did obtain positive readings for trace amounts of HIV RNA and DNA in some blood and tissue samples (the vast majority of the tests, including those looking for replication-competent virus in large volumes of cells, were negative). One scientist in particular, who was not involved in the research, made wild-eyed claims—via press release, no less—that the findings meant that Brown was either not really cured or potentially had been re-infected. The results of the study were published yesterday in the open access journal PLoS Pathogens, and the authors offer a sober discussion of their implications. In particular, they highlight the difficulty of formally proving a cure using current virologic assays that are operating at the limits of their sensitivity. Rather, they suggest, the waning of immune responses to HIV in Timothy Brown (both antibodies and T cells) may represent the clearest confirmation that he is indeed cured. READ MORE
4/12/13 (with updates on 4/20/13, 4/29/13, 5/2/13 & 5/3/13) - The April issue of Human Vaccines & Immunotherapeutics features an excellent open access review by Thomas Rasmussen and colleagues describing approaches to eliminating HIV reservoirs that are advancing into clinical trials. READ MORE
4/9/13 - It’s well documented that T-cell immune responses targeting HIV can cause selection of viral variants that evade recognition (immune escape). But some studies have reported that, surprisingly, HIV variability in regions targeted by T cells is lower compared to other locations in the genome, a phenomenon not seen with other RNA viruses. In a paper published last week in PLoS Biology, Rafael Sanjuán and colleagues offer a potential explanation. Based on mathematical modeling studies, they suggest that selection may favor the conservation of parts of HIV that efficiently activate CD4 T cells, because this provides the virus with target cells in which to replicate. This suggestion is consistent with evidence that HIV itself is often a major driver of immune activation (e.g. activation precipitously declines when HIV replication is suppressed by therapy), and with the finding that HIV preferentially infects HIV-specific CD4 T cells. The theory also fits with recent data showing that SIV can cause immune activation and progression to simian AIDS in the absence of any contribution from microbial translocation. READ MORE
4/4/13 - In recent years, new technologies have facilitated the discovery of an expanding number of antibodies capable of neutralizing a broad array of primary HIV isolates from different clades. As covered previously on the blog, these broadly neutralizing antibodies (BnAbs) have been fished from the plasma of individuals with chronic HIV infection and, in most cases, do not seem to be present at titers sufficient to control viral load or retard disease progression; however, there are reasons to hope that if similar antibodies could be induced by vaccination, they could rebuff the relatively small amount of HIV that enters the body during a typical exposure. READ MORE
3/21/13 - Coverage of some subjectively selected presentations from the recent CROI meeting in Atlanta, in addition to the prior post on the case report of a potentially functionally cured infant. READ MORE
3/15/13 - Over the years, a number of small studies have been published suggesting that there might be benefits associated with probiotic and/or prebiotic supplementation in people with HIV infection. Probiotics typically comprise live microbes that play a key role in maintaining gut health—commonly known as “good bacteria”—while prebiotics are food ingredients intended to stimulate the expansion and activity of these bacteria. The past decade has seen a renewed interest in gut health in HIV infection due to evidence that the virus severely depletes CD4 T cells in the GI tract, leading to diminished immune surveillance, compromised gut-wall integrity, and microbial translocation (the leakage of gut bacteria into the systemic circulation). Additionally, suppression of HIV replication by antiretroviral therapy (ART) does not necessarily restore gut CD4 T-cell numbers, and markers of microbial translocation have been associated with poor immune reconstitution despite ART. READ MORE
3/2/13 - On Monday March 4th at the Conference on Retroviruses and Opportunistic Infections (CROI) in Atlanta, details were presented on a case of a potential “functional cure” of HIV infection in an infant. The story has already broken widely in the media due to a CROI press conference held on Sunday afternoon, during which the researcher describing the case, Deborah Persaud, gave a preview of the data. The webcast of Persaud’s talk is now available for viewing online (it is the 7th presentation in the session entitled “Is There Hope for HIV Eradication?”). READ MORE
2/6/13 - When it comes to susceptibility to HIV infection, not all CD4 T cells are created equal. There are a variety of factors that have been shown to influence how readily HIV gains entry and replicates, with the best-described distinction being between activated CD4 T cells, which are highly susceptible, and resting CD4 T cells, which are relatively resistant The particular types of cytokines and chemokines that a CD4 T-cell makes have also been shown to influence the efficiency of HIV infection. Less well understood is the influence of antigen specificity—the pathogen being targeted by the CD4 T cell. Evidence has been published showing that TB-specific CD4 T cells are highly susceptible, whereas those responding to the viral infection CMV are relatively resistant (with this resistance being associated with the release of beta-chemokines capable of binding the CCR5 receptor and blocking HIV entry). A study by Haitao Hu and colleagues from the US Military HIV Research Program has now explored this issue further by looking at the susceptibility of various pathogen-specific CD4 T cells and the relationship with the genes that the different cells express. READ MORE
1/29/13 - Several years ago scientists discovered a link between T-cell dysfunction and the expression of a receptor named PD-1 on the T-cell surface. The initial discovery related to T cells in mice that had become functionally compromised due to battling a chronic viral infection (LCMV); it turned out these exhausted T cells expressed very high levels of PD-1. Receptors like PD-1 can essentially be thought of as antennae on the outside of the cell that can interact with, and respond to, specific signaling molecules in the cell’s environment. Depending on the signal, the receptor may sink back inside the cell to convey a message to the command center in the nucleus. This message then in turn affects the behavior of the T cell and may lead to greater or lesser expression of the receptor. The PD-1 receptor can interact with at least two molecules (described as ligands), PD-L1 and PD-L2. Because high levels of PD-1 expression were associated with reduced T-cell function, researchers studied the effects of administering an antibody that targets PD-1 and thereby blocks its ability to interact with its ligands. The results of this experiment drew a lot of attention, because the strategy successfully rejuvenated the exhausted T cells and improved their ability to control LCMV replication. Similar laboratory findings were subsequently reported with T cells targeting cancers, leading to the development of anti-PD-1 antibodies as cancer therapies (an approach that has begun to show some success in human trials). PD-1 has also since been found to be highly expressed on exhausted HIV-specific T cells in humans, and a small study in macaques reported that PD-1 blockade reduced SIV viral load. READ MORE
1/29/13 - On January 16th, a scientist named David Harrich and his institution, the Queensland Institute for Medical Research (QIMR) in Brisbane, Australia, issued a press release invoking the word cure in an effort to publicize a scientific paper containing in vitro (lab dish) study results of uncertain significance at best. The release spawned a maelstrom of misleading media coverage that has continued to swirl for weeks afterward. READ MORE
1/18/13 - In November 2011, the laboratory of Nobel laureate David Baltimore published encouraging results from humanized mouse studies of an approach to HIV prevention they have named vectored immunoprophylaxis (assigned the slightly uncomfortable acronym VIP). The strategy involves the use of adeno-associated virus (AAV) as a vector to deliver genes that make broadly neutralizing antibodies against HIV after delivery into muscle tissue. The ultimate goal is to make an end-run around the well-documented challenges associated with designing a vaccine capable of persuading the human immune system to generate broadly neutralizing antibodies. Instead, AAV would serve as a factory for the production of these antibodies, a task to which it is thought to be well-suited because it persists for very long periods in the episome of cells (but does not integrate into the genome). The idea was first developed by Phillip Johnson at the Children’s Hospital of Philadelphia, who is collaborating with the International AIDS Vaccine Initiative (IAVI) to launch phase I human testing of an AAV encoding the broadly neutralizing antibody PG9 (listed as AAV1-PG9 on the IAVI portfolio page). Johnson’s preclinical research in the SIV/macaque model has been covered previously on the blog. READ MORE
1/15/13 - A study published in the January 2nd issue of Science Translational Medicine reports that a dendritic cell (DC)-based therapeutic HIV vaccine was able to significantly lower viral load after an antiretroviral therapy (ART) interruption, albeit only transiently. The publication drew considerable press coverage; most of it reasonably accurate although some headline writers got carried away (while potentially representing a step forward for therapeutic HIV vaccine research, the results are not a “huge breakthrough” as one headline stated). READ MORE
1/7/13- One of the less well-publicized consequences of the persistent immune activation caused by HIV infection is a type of scarring damage to lymph tissues described as fibrosis. Some early studies of lymph nodes from HIV-infected individuals reported evidence of this problem, but it wasn’t until the publication of a study by the research group of Ashley Haase in 2002 that a connection was made between the extent of fibrosis (as measured by deposition of collagen) and maintenance of CD4 T cell numbers. Haase and colleagues showed that there was an inverse correlation between lymph node fibrosis and the number of CD4 T cells measurable in the same node. Importantly, they also found that the degree of fibrosis was significantly associated with the magnitude of CD4 T cell increases after initiation of antiretroviral therapy, with greater fibrosis linked to poorer CD4 T cell recovery. READ MORE
12/31/12 - In both HIV and SIV infections, it has been shown that the most rapid and extensive loss of CD4 T cells occurs in the gut. As a consequence, a theory has emerged positing that gut CD4 T cell depletion plays a central causative role in driving HIV pathogenesis; the proposed mechanism is that gut wall integrity becomes compromised, leading to the leakage of normally friendly bacteria from the digestive tract and into systemic circulation, which in turn contributes to persistent immune activation and, ultimately, progression to AIDS. However, some scientists have remained skeptical of this theory, suggesting instead that gut CD4 T cell depletion is an effect of HIV infection but not necessarily the primary cause of disease progression. The skeptics have gained some support from studies showing that severe gut CD4 T cell depletion occurs during acute SIV infection in monkey species that experience no apparent ill effects from the virus (sooty mangabeys and African green monkeys). A paper published recently in the Journal of Virology now shows that the opposite phenomenon is also possible: a modified SIV that does not cause loss of gut CD4 T cells nevertheless causes persistent immune activation and progression to simian AIDS in rhesus macaques. READ MORE
12/31/12 - Following up on the recent post on T follicular helper cells (TFH), a study published on December 17th in the Journal of Experimental Medicine reports that TFH represent a major site of HIV replication and persistence. The finding is not necessariy surprising, because lymph node studies conducted in the late 1980s and early 1990s showed that CD4 T cells in areas named germinal centers bore a great burden of HIV infection, and it is now known that this is where TFH locate during an immune response. But it was not previously understood that these CD4 T cells comprise a discrete subset, and TFH are now becoming increasingly well characterized in terms of both identifying features (such as surface markers and cytokine secretion) and their function in providing help to B cells. READ MORE
11/27/12 - Among the many tasks of the immune system, the responsibility for recognizing and killing virus-infected cells largely falls to the subset of CD8 T cells designated cytotoxic T-lymphocytes (CTL). The question of whether CD4 T cells (traditionally called just “helper” cells) can exert cytotoxic functions has historically been controversial, but over the past decade studies have convincingly documented the existence of cytotoxic CD4 T cell responses in a variety of different settings, including HIV and SIV infection (as previously covered on this blog). A new paper in the open-access journal Retrovirology from Jonah Sacha’s research group at Oregon Health and Science University now reports that not only are cytotoxic CD4 T cell responses detectable in macaques controlling a pathogenic SIV isolate, but they can drive the selection of immune escape mutations. As the authors note, this represents compelling evidence that CD4 T cells can directly suppress viral replication. READ MORE
11/26/12 - T follicular helper cells (TFH) are a subset of CD4 T cells that reside almost exclusively in the lymph nodes, where they specialize in helping B cells generate antibodies. In a testament to the complexity and difficulty of studying the immune system, TFH were only identified as a discrete subset of CD4 T cells at the turn of the millennium. Since that time, several features that define TFH have been described, including high levels of the chemokine receptor CXCR5, expression of the PD-1 molecule, secretion of the cytokine IL-21 and upregulation of the Bcl-6 gene. Studies have also found TFH to be important for driving the process of affinity maturation (wherein B cells producing antibodies with increased affinity for their antigen target are progressively generated and selected), and for supporting the development of long-lived memory B cells. READ MORE
11/14/12 - In prior posts I’ve written about research from the laboratories of Mario Ostrowski and Doug Nixon looking at the effect of HIV infection on human endogenous retrovirus (HERV) protein expression. This work, led by Brad Jones and Keith Garrison, has shown that the liberating effects of the HIV Vif protein can cause normally inactive HERV genetic sequences to produce proteins in cells infected by HIV. These proteins can then be processed and presented as antigens and, as a consequence, HERV-specific CD8 T cell response are detectable in some individuals with HIV. However, up until now there has been no direct evidence that HERV-specific CD8 T cell responses can actually recognize and kill HIV-infected CD4 T cells. A paper just published in the Journal of Clinical Investigation addresses this information gap, demonstrating that CD8 T cells specific for a HERV-K(HML-2) epitope are able to recognize and kill CD4 T cells infected with an array of HIV-1, HIV-2 and SIV isolates (albeit with varying levels of effectiveness depending on the specific isolate). READ MORE
10/17/12 - In a review article in the open-access journal Retrovirology, Guido Vanham and Ellen Van Gulck provide a detailed accounting of the multitude of immune-based therapy (IBT) studies that have been conducted over the years (both in people with HIV and the SIV/macaque model). The authors were prompted by the recent resurgence in interest in attempting to induce immune control of HIV in the absence of ongoing antiretroviral therapy (ART), a goal that is now described as achieving a “functional cure.” While the term is new, the goal itself is not: in the late 1990s, it was described more circumspectly as “remission.” Unfortunately, the best results to date from IBT studies involve small and transient diminutions in viral load associated with receipt of some therapeutic vaccine candidates. Despite the disappointments, attempts to achieve more robust control of HIV continue; Vanham and Van Gulck are pursuing a therapeutic vaccine approach involving delivery of HIV antigens to dendritic cells using messenger RNA (mRNA). READ MORE   
9/14/12 - The AIDS Vaccine 2012 conference took place in Boston September 9-12, organized by the Global HIV/AIDS Vaccine Enterprise, the Ragon Institute of MGH, MIT and Harvard, and the Havard Center for AIDS Research. Webcasts of all the conference sessions are now available online, and the abstracts have been posted as a a supplement to the open access journal Retrovirology. Topics of discussion included follow-up from the RV144 Thai vaccine trial (including recently published evidence that protection may have been limited to HIV variants with specific genetic sequences in the V2 region of the viral envelope), new approaches to the induction of broadly neutralizing antibodies, the potential importance of a recently identified CD4 T-cell subset named T follicular helper cells, and opportunities for synergy between vaccine research and efforts to cure HIV infection. READ MORE
9/12/12 - In the early 1990s, the research group of Frank Plummer at the University of Manitoba drew considerable attention—and some controversy—when they reported that, among a large cohort of female sex workers in Nairobi, a subset showed evidence of resistance to HIV infection. The evidence emerged over the course of a long-term study that found that women starting sex work faced a very high risk of seroconverting in the first two years. However, for a subset of women who remained HIV-negative, the risk of becoming infected subsequently declined significantly over time, which Plummer and colleagues interpreted as evidence of resistance to acquisition. Despite initial skepticism, the findings prompted efforts to identify individuals with possible resistance to HIV in other settings, such as among serodiscordant couples (in which one partner is HIV-positive and the other HIV-negative). There is now a substantial amount of literature on the topic, as well as ongoing workshops and research collaborations, but one of the challenges in the field is that there are no widely accepted criteria for defining high exposure to HIV (an important part of assessing whether an individual may be resistant as opposed to simply unexposed). READ MORE

Immune Activation, Inflammation and HIV Acquisition Risk
8/21/12 - The geographic variation in the risk of HIV acquisition among heterosexuals has prompted extensive speculation and debate as to the underlying causes. The lack of a clear explanation has even fueled conspiracy theories, playing a prominent role in Thabo Mbeki’s disastrous embrace of AIDS denialism in South Africa and driving a campaign that—in the face of a mountain of evidence to the contrary—insists that non-sexual transmission is the answer. It has not helped that much of the research on the subject has focused on behavior, with hypotheses such those based on concurrent sexual partnerships being aggressively promoted by certain individuals even though many view the evidence supporting them as slim to non-existent (for a recent critique, see “HIV, logic and sex in Africa” by Lucy Allais and Francois Venter). Relatively speaking, biological explanations have received less attention, despite the fact that it is well known that the immunological environment in which HIV finds itself has a huge impact on its ability to replicate and thrive. Only a handful of published studies have looked at how geographic location can impact levels of immune activation, finding that background levels are significantly higher in locations on the African continent compared to Europe and the US. The first such study to specifically analyze immune activation in the genital tract (comparing women in Kisumu, Kenya and San Francisco, USA) was published only two years ago. READ MORE

8/13/12 - At the recent 19th International AIDS Conference in Washington DC (AIDS 2012), the research effort to develop a cure for HIV infection attained a higher profile than it ever has in the past. A confluence of factors contributed: the International AIDS Society (IAS) officially launched their Global Strategy “Towards an HIV Cure,” in conjunction with a two-day symposium that immediately preceded the main conference. The IAS effort involves a multiplicity of stakeholders—including TAG—and a global consultative process that has spanned the two years since the first workshop on the topic in Vienna in 2010. In addition to the extensive press coverage of the IAS-led effort, the one individual considered cured of HIV, Timothy Brown, was in DC and gave a number of press interviewsREAD MORE
7/27/12 - This past Wednesday in the journal Nature, Nancy Archin and colleagues from the laboratory of David Margolis published results from a trial investigating whether the approved cancer drug vorinostat can reverse HIV latency. Vorinostat (also known as SAHA, trade name Zolinza) belongs to a group of compounds called histone deacetlyase (HDAC) inhibitors. Histone deacetylases are a class of cellular enzymes involved in condensing DNA and repressing gene expression. In laboratory experiments, inhibiting histone deacetylases appears to free latent HIV from lockdown, causing viral RNA to be produced. HDAC inhibitors have therefore emerged as lead candidates for depleting latent HIV reservoirs, a task that is widely believed to be an important step along the path to a cure. READ MORE
7/26/12 - The extent to which virus-specific CD8 T cell responses contribute to control of viral load and prevention of disease progression in HIV infection has long been a subject of conflicting data and controversy. Early tests of the ability of CD8 T cells to kill target cells expressing HIV antigens were misleading because they relied on extended culture with IL-2, a process that turned out to have restorative properties on otherwise dysfunctional cells. The advent of class I MHC tetramers, which facilitate the counting of CD8 T cells specific for individual HIV epitopes, was an advance but also initially caused confusion: an early paper using tetramers reported an inverse correlation between CD8 T cells specific for epitopes from HIV Gag and Pol and viral load, but a subsequent more comprehensive analysis of CD8 T cell responses to all viral proteins found the opposite: a positive correlation with viral load. READ MORE
6/29/12 - In August of 2011, researchers from the laboratory of David Baltimore published a high profile paper in the journal Nature suggesting that cell-to-cell HIV transmission facilitates ongoing viral replication in the face of antiretroviral therapy (ART). The authors proposed that this might represent a mechanism that sustains the reservoir of HIV-infected cells in people on long-term ART. READ MORE
6/9/12 - On Friday at the International Workshop on HIV & Hepatitis Virus Drug Resistance and Curative Strategies in Sitges, Spain, Steve Yukl from UCSF presented new data on the case of Timothy Brown, the “Berlin Patient." Yukl described multiple experiments performed by several independent laboratories with the aim of searching intensively for any signs of residual HIV infection in plasma, peripheral blood mononuclear cells (PBMC) and biopsies from the gut and cerebrospinal fluid (CSF). The nature of these analyses is a testament to Brown’s extremely laudable willingness to undergo an array of unappealing procedures in order to advance research into curing HIV. READ MORE
5/4/12 - Following on the heels of the prior post, a new paper published online today in the Journal of Infectious Diseases confirms that uncircumcised MSM with pre-existing antibody responses to Ad5 experienced an enhanced risk of HIV acquisition in the STEP trial. Importantly, however, this study documents that the effect has waned over time. READ MORE

Behavior and Circumcision Status Do Not Explain Increased Risk of HIV Acquisition Associated with Ad5-Based Vaccine
4/20/12 - In September 2007, the HIV vaccine field received an unexpected setback when it was announced that the phase IIb efficacy trial of a candidate developed by Merck was being stopped early due to lack of efficacy. The trial was conducted by the HIV Vaccine Trials Network (HVTN) and was referred to as the STEP study. The Merck vaccine aimed to stimulate T cell immunity against HIV, and used a novel attenuated adenovirus serotype 5 (Ad5) vector to deliver the HIV antigens Gag, Pol and Nef. The Ad5 approach was selected because it induced unprecedented levels of HIV-specific CD8 T cell responses in phase I and II trials, with >70-80% of recipients responding (the previous best was a dismal 20-30% of recipients showing low-level CD8 T cell responses after immunization with an ALVAC vector). Although HIV-specific CD8 T cell responses were not anticipated to protect against acquisition of HIV infection, evidence indicated that they might be able to suppress HIV replication and thereby increase the chances of vaccine recipients becoming elite controllers if they became HIV-infected. READ MORE

HIV-Killing Stem Cell Paper Glosses Over Key Caveat
4/20/12 - A recent paper describing the engineering of stem cells to generate HIV-specific CD8 T cells has drawn considerable media attention and, regrettably but not untypically, many of the stories are profoundly misleading. Examples of headlines include:

“Scientists engineer stem cells which suppress HIV: cure for AIDS possible”
“New breakthrough shows stem cells can be engineered to fight HIV!‎”
“UCLA-engineered stem cells seek out and kill HIV in living organisms”
The last example is the headline of the UCLA press release that accompanied publication of the paper in PLoS Pathogens. It is not inaccurate, but what is likely not apparent to many people is that just about everyone’s stem cells make CD8 T cells with HIV-specific T cell receptors (TCRs) that would have similar potential to suppress HIV replication in humanized mice (the model used in the study). My stem cells have probably made some while I’m writing this post and the same is true for anyone reading it. Although some TCRs appear particularly adept at recognizing HIV antigens, it is not the lack of HIV-specific CD8 T cells with appropriate TCRs that underlies the inability to control HIV replication in most people; rather, the preponderance of evidence indicates that the functionality of the HIV-specific CD8 T cell response is severely compromised. READ MORE
4/16/12 - On March 29th, PLoS Pathogens published a paper reporting that women superinfected with two HIV variants are more likely to generate antibody responses capable of neutralizing a broad array of viral strains (known as broadly neutralizing antibodies or bNAbs). The work was conducted by the laboratory of Julie Overbaugh at the Fred Hutchinson Cancer Research Center (FHCRC) in collaboration with the University of Nairobi. FHCRC issued a press release to publicize the work entitled “Study finds HIV ‘superinfection’ boosts immune response.” In retrospect, this may have been a poor choice of words, as it can easily be misinterpreted to suggest that the immune response of the superinfected women was boosted in a way that was beneficial to them; today at least one press story has done just that, stating: “A new study suggests that women who have been infected by two variations of HIV may have a better chance of suppressing the virus then those only infected with one.” This is completely untrue. READ MORE
Study Questions Role of HDAC Inhibitors in HIV Cure Research
3/30/12 - The Keystone Symposia conference “Frontiers in HIV Pathogenesis, Therapy and Eradication” is taking place this week in Whistler, Canada. A poster presentation at the meeting by Jana Blazkova from the laboratory of Anthony Fauci at the National Institute for Allergy and Infectious Diseases (NIAID) seems likely to place a proverbial cat among the pigeons when it comes to the use of HDAC inhibitors as a strategy to reverse latent HIV infection. READ MORE

Inching Forward with HIV Vaccines: Digesting Envelope Decoys
3/21/12 - At the recent CROI in Seattle, antibody expert Dennis Burton compared HIV’s envelope structure to an assemblage of Tootsie Pops. In this analogy, the parts of HIV’s envelope that are susceptible to neutralizing antibodies are represented by the chocolate contained inside the Tootsie Pop, and the carbohydrate molecules that act as decoys (by inducing ineffective non-neutralizing antibody responses) are represented by the coating of candy that surrounds the chocolate filling. Last year on the blog I wrote about two studies exploring a new strategy for dealing with HIV’s shielded envelope: using certain enzymes to digest—essentially eat away—the carbohydrate covering so that neutralizing antibody targets are revealed. READ MORE
19th Conference on Retroviruses & Opportunistic Infections
3/14/12 - The 19th annual Conference on Retroviruses & Opportunistic Infections (CROI) took place last week from Monday through Thursday in Seattle. As has consistently been the case in recent years, the organizers have done a commendable job in making the conference accessible online: all sessions—including poster discussions—are available via webcast, and very few presenters have failed to make their slides available. READ MORE
Report and Commentary from the Fifth International Workshop on HIV Persistence during Therapy
2/7/12 - Inaugurated in 2003, the bi-annual International Workshop on HIV Persistence during Therapy (aka “the persistence workshop”) is the brainchild of researcher Alain Lafeuillade. The meeting presaged the recent explosion of interest in pursuing a cure for HIV infection, a pursuit many had considered quixotic until the case of Timothy Brown came to light in 2008. As has been extensively documented, Brown’s apparent cure resulted from a debilitating odyssey of treatments required for the grim diagnosis of acute myelogenous leukemia, enhanced with a mix of insight and good fortune on the part of his doctor Gero Hutter, who was able to provide a stem cell transplant from a donor lacking the major HIV co-receptor CCR5. The sea change wrought by this fortuitous “proof of concept” was much in evidence at the 2011 persistence workshop this past December; the tentative forays into basic science that were once emblematic of the field are now mixed together with more ambitious plans for advancing ideas into the clinic. Perhaps most strikingly, two large pharmaceutical companies—Gilead and Janssen/Tibotec—described their use of industrial scale screening to search for compounds that are active against latent HIV. This represents an unprecedented expansion of efforts once confined to under-resourced academic labs. READ MORE
Adenovirus Vaccine Addendum: Chimp-Based Vector Shows Promise
1/27/12 - Following on from the recent post about the promise and potential pitfalls of adenovirus-based vaccine vectors, an open access paper published on Tuesday in the Journal of Infectious Diseases reports data that appear to fall firmly on the promise side of the balance sheet. Researchers from the laboratory of Adrian Hill at the University of Oxford describe results of a phase I trial of a chimpanzee adenovirus type 63 (ChAd63) vector encoding malaria antigens, showing that the vaccine induced CD8 and CD4 T cell responses in all recipients. The magnitude of the responses (as measured by ELISPOT assays) was also impressive; the researchers note they were superior to those observed with Merck’s Ad5-based HIV vaccine candidate. Safety compared favorably to other adenovirus vectors. READ MORE
New Study Undermines Claim that Hematopoietic Progenitor Cells Represent an HIV Reservoir
1/24/12 - Back in March 2010, the laboratory of Kathleen Collins at the University of Michigan published a paper in Nature Medicine suggesting that CD34+ hematopoietic progenitor cells can be infected with HIV and represent a reservoir of virus in some individuals on ART (4 out of 9 participants in their study). The paper generated a great deal of press coverage at the time, with headlines such as “HIV Hides Out in Bone Marrow Cells” and multiple outlets featuring interviews with Collins describing the findings. Today in the Journal of Infectious Diseases, the laboratory of Bob Siliciano at Johns Hopkins—which has been investigating HIV persistence and latency since the mid-90s—offers compelling evidence that HIV infection of CD34+ hematopoietic progenitor cells is an extremely rare event (if it occurs at all). READ MORE
The Promise and Pitfalls of Adenoviruses as Vaccine Vectors
1/20/12 - A bevy of recently published papers address the use of adenoviruses as vaccine vectors, illuminating both the promise of the approach and some previously unappreciated pitfalls. READ MORE
01/04/12 - Previously on the blog I’ve covered studies addressing the under-researched role of genital tract immune activation in increasing the risk of HIV acquisition, and the potential link between this phenomenon and global variation in HIV prevalence. A related issue is the impact of genital infections on the probability of acquiring HIV. Several recent papers (abstracts and links below) draw attention to the specific contributions of Mycoplasma genitalium and Schistosoma haematobium in this regard, highlighting the importance of considering these factors in the context of HIV prevention, and also emphasizing the need to better understand their contribution to the increased risk of heterosexual HIV transmission in sub-Saharan Africa. READ MORE
Maxed Out: Treatment Intensification Studies Report No Effect on Residual HIV Levels or Immune Activation
11/28/2011 - Scientists continue to wrestle with the question of whether combination antiretroviral therapy (ART) completely suppresses HIV replication in most recipients. The development of ultra-sensitive “single copy” viral load tests (which can measure down to 0.3 HIV RNA copies in a milliliter of blood) has revealed that most individuals with levels below 50 copies show evidence of persistent residual viral RNA. There are two potential (non-exclusive) sources: long-lived, chronically infected cells containing integrated viral DNA which produce RNA copies either intermittently or continuously—such cells would be impervious to the effects of current antiretroviral therapies—or low-level HIV replication, in which new RNA copies are produced which go on to infect other cells. In the latter case, intensifying ART with additional drugs would be predicted to reduce the amount of residual viral load and the number of cells containing integrated HIV DNA. READ MORE

Underestimating the (CD4 T Cell) Help
11/02/2011 - Following on from the recent post about the importance of virus-specific CD4 T cells in controlling SIV, another new paper adds to the evidence that they also play an important role in HIV infection. Conducted by the laboratory of Hendrik Streeck at the Ragon Institute in collaboration with David Heckerman at Microsoft, the study "represents the first comprehensive analysis conducted at the population level to identify HIV-specific CD4 T cell responses to individual HIV protein subunits and peptides and to elucidate the immunodominance profile of these responses in a large cohort of HIV-controllers and progressors." Given that there has long been an appreciation of the importance of CD4 T cells in immunity against many pathogens, it seems quite remarkable that it has taken until 2011 for such a study to be undertaken. The authors themselves note: "surprisingly little is known about the presence of these responses in the setting of HIV infection." READ MORE

New Studies on HIV and the Diseases of Aging
11/01/2011 - The December 1st issue of Clinical Infectious Diseases contains a raft of papers addressing the issue of HIV and aging (abstracts and links below). A report from the Swiss HIV Cohort Study documents that illnesses typically associated with aging are now the most common causes of morbidity in their cohort, which contains an increasing proportion of individuals aged 50 or older (see graph). In contrast, opportunistic infections make only a minor contribution in the current era of effective antiretroviral therapy (ART). An accompanying editorial by Mike Saag highlights the implications for providing appropriate multidisciplinary care to people with HIV as they age. READ MORE

Humanized Mouse Models of HIV Latency
10/21/2011 - A major obstacle in the pursuit of a cure for HIV infection is the existence of long-lived cells containing viral DNA integrated into the cellular genome. These latently infected cells spark renewed rounds of viral replication when suppressive antiretroviral therapy (ART) is interrupted. Researchers are now aiming to develop strategies to purge latently infected cells, and these efforts would be greatly aided by animal models that recapitulate—at least to some extent—what occurs in humans. READ MORE

Open Access Articles on HIV in Cold Spring Harbor Perspectives
10/20/2011 - The journal Cold Spring Harbor Perspectives is offering several free review articles on HIV research, see abstracts and links. READ MORE

Assessing the Role of Virus-Specific CD4 T Cells in Controlling SIV
10/20/2011 - One of the studies presented at the recent AIDS Vaccine 2011 conference has now been published in the Journal of Clinical Investigation. It addresses a longstanding uncertainty in HIV research regarding the role of virus-specific CD4 T cells in controlling viral replication. On the one hand, basic immunology research conducted over the last two decades has made it increasingly clear that CD4 T cell responses play a vital role in sustaining functional CD8 T cell and B cell responses in most settings. In HIV infection, however, it is known that HIV-specific CD4 T cells are preferentially infected by the virus, raising the concern that these responses may enhance rather than limit viral replication. Although the issue is still debated, the preponderance of evidence now suggests that functional, broadly targeted—and particularly Gag-specific—HIV-specific CD4 T cells are vital for sustaining effective HIV-specific CD8 T cell responses and are therefore typically beneficial rather than harmful. READ MORE

Lost In Translation: Crazy Claims About MVA-B HIV Vaccine Candidate
9/30/2011 - This past Wednesday, September 28, the Spanish Superior Scientific Research Council (CSIC, Consejo Superior de Investigaciones Científicas) issued a press release about the results of a phase I HIV vaccine trial involving 30 people. The release refers to two recently published papers, one made available online by the journal Vaccine on September 9, the other by J. Virology on August 24 (abstracts and links below). The trial used a very common vector, modified vaccinia Ankara strain (MVA, a highly attenuated member of the poxvirus family), to deliver HIV antigens, and studied the resulting immune responses (24 participants received vaccine, 6 placebo). The results were a little better than those obtained with some other MVA vectors, but similar to responses seen with adenovirus-based vectors like the Ad5 HIV vaccine developed by Merck, which failed to show any efficacy at either preventing or controlling HIV infection in a widely-publicized phase IIb trial (the STEP study). So far, so average. But the press release went a little overboard in attempting to sell the results to the media, and the result has been some of the most woefully misleading and erroneous coverage of HIV vaccine research in recent memory. READ MORE

HIV-Specific CD4 T Cells Harbor the Majority of Latent Virus: Implications for Therapeutic Vaccines
9/26/2011 - A new paper in the journal AIDS Research and Human Retroviruses reports that the majority of CD4 T cells harboring latent HIV infection are specific for HIV antigens (as opposed to other common antigens such as PPD, CMV or influenza). Conducted by Ashwini Shete and colleagues from the National AIDS Research Institute in India, the study investigated the capacity of a variety of antigens to stimulate HIV replication in CD4 T cells from people with HIV (both on and off ART). In untreated individuals, Env and Pol antigens invoked significantly more HIV expression than other HIV and non-HIV antigens. In a cohort of 18 individuals on ART, HIV replication was induced significantly more frequently after stimulation with Env, Pol and Gag compared to other HIV and non-HIV antigens. Notably, a minority of participants did show evidence of lower-frequency infection of cells specific for peptides from PPD, influenza, EBV and CMV. The findings echo and extend those reported in 2002 by Audreya Demoustier and colleagues (available in full text online), which documented preferential stimulation of latent HIV with a less diverse array of viral antigens (p24 and Nef). READ MORE

Abstracts from the AIDS Vaccine 2011 Conference
The abstract book from the AIDS Vaccine 2011 conference, which took place last week in Bangkok, is now available free online via the journal AIDS Research & Human Retroviruses. Appended below is a highly subjective selection of highlights, including new data on the role of CD4 T cell responses in control of HIV, an intriguing study linking the nucleotide composition of lentiviruses to their pathogenicity, and results from animal modelers attempting to recapitulate both the recent RV144 vaccine trial in Thailand and the STEP trial of Merck’s now-discontinued HIV vaccine candidate. Links to e-Posters are included if they are available on the conference website. READ MORE

Immune Correlates of HIV Infection Risk in the RV144 Vaccine Trial
9/15/2011 - On Tuesday at the AIDS Vaccine 2011 conference in Bangkok, Barton Haynes described the initial results of a mammoth effort to uncover immune correlates of protection in the RV144 vaccine trial (the presentation is available online via the conference website). As reported in the New England Journal of Medicine in 2009, the trial demonstrated a very slight but statistically significant degree of efficacy in reducing HIV infection risk; there were 51 infections in the vaccine group compared to 74 in the placebo group, indicating the vaccine reduced HIV acquisition by 31.2% (95% confidence interval: 1.1 to 52.1; p=0.04). Of potential importance, the reduction in risk was greatest in the first year, during which there were 12 infections among vaccine recipients compared to 30 in the placebo group. Over the subsequent 2.5 years of follow up, there were an additional 39 infections in the former group and 45 in the latter (essentially no difference). READ MORE

HIV Replication in CCR5-Expressing T Cells
8/22/2011 - A new study from the laboratory of Elizabeth Connick at the University of Colorado takes a detailed look at HIV replication in activated T cells. The study demonstrates that the chemokine receptor CCR5 is highly expressed by CD4 T cells displaying dual activation markers, HLA-DR and CD38, and that these cells are the major source of virus in lymph node samples from infected individuals. Importantly, there were differences observed between viral replication studied in lab culture conditions (in vitro) compared to the lymph node samples: the bulk of the CD4 cells replicating HIV in vitro were CD38+ but lacked HLA-DR and did not preferentially express CCR5. READ MORE

Exercise as Immune-Based Therapy
8/15/2011 - Many studies have reported that regular exercise confers health benefits and that, conversely, a sedentary lifestyle is a major risk factor for morbidity and mortality (particularly from cardiovascular disease). In recent years, researchers have begun to look more specifically at the immunological effects of exercise. The scientist Richard Simpson, formerly at Napier University in Edinburgh and now based at the University of Houston in Texas, has pioneered the exploration of the intersection between exercise and immune senescence. This research is potentially relevant to HIV infection because, as reported in some prior blog posts (see the immunosenescence category), senescent immune cells—particularly CD8 T cells—accumulate over time and may persist despite antiretroviral therapy. Simpson’s recent work suggests that exercise mobilizes senescent immune system cells from the tissues into the blood and increases their death by apoptosis; if confirmed this may offer both a more practical approach to addressing senescence than the idea of physically removing cells, and could also explain some of the positive contributions of exercise to healthy aging that have been described in the literature. READ MORE

Mapping the Long Genetic Road to Broadly Neutralizing Antibodies
8/12/2011 - Over the past couple of years, several new antibodies capable of neutralizing a broad array of HIV isolates have been discovered. As mentioned in prior posts about these discoveries, one common feature of these antibodies is that the B cells that produce them have undergone an unusual degree of somatic hypermutation—a process in which the cell’s antibody-producing genetic code is progressively revised in order to increase the affinity of the antibody for its target. The genetic code that the B cell starts out with is called the germline sequence, and it is typically altered by around 5-15% to produce antibodies against common infections, whereas this figure ranges from 19-46% for the broadly neutralizing antibodies against HIV that have been identified. Antibodies targeting the part of the HIV envelope that binds to the CD4 receptor, such as the recently discovered VRC01, are at the extreme end of this scale (showing sequence alterations of 40-46%). READ MORE

Monkey Viral Reservoir Study Goes for Gold
7/26/2011 - A small study of auranofin, a gold-based drug developed to treat rheumatoid arthritis, suggests it may be able to reduce the reservoir of SIV-infected CD4 T cells in macaques on antiretroviral therapy (ART). The paper appears in the July 17th issue of the journal AIDS, and previously generated some excitable media coverage when it appeared online-ahead-of-print in April (the researchers issued a press release at the time entitled “Gold-based Drug May Pave the Way to a Cure for AIDS”). The mechanism of action of auranofin is not fully understood, but it has been shown to inhibit proliferation of CD4 T cells and thus may prevent the expansion of latently infected cells and/or shift these cells from a long-lived to short-lived phenotype. The authors note that there is one published case report on the use of auranofin in an individual with HIV, and it did not show an adverse effect on overall CD4 T cell numbers. READ MORE

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