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By Richard Jefferys, Project Coordinator
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.
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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.
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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.
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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.
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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.
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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.
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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?”).
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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.
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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.
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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.
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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.
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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).
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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.
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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.
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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.
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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.
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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.
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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).
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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).
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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).
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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 interviews.
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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.
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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.
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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 MORE6/9/12 - 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.
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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.
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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.
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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.
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Study Questions Role of HDAC Inhibitors in HIV Cure Research3/30/12 - 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.
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Inching Forward with HIV Vaccines: Digesting Envelope Decoys3/21/12 - 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.
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Report and Commentary from the Fifth International Workshop on HIV Persistence during Therapy2/7/12 - 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.
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Adenovirus Vaccine Addendum: Chimp-Based Vector Shows Promise1/27/12 - 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.
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New Study Undermines Claim that Hematopoietic Progenitor Cells Represent an HIV Reservoir1/24/12 -
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).
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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.
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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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