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Michael Palm Basic Science, Vaccines, and Cure Project Blog

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By Richard Jefferys, Project Coordinator

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 (http://bnaber.org) 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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