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TAG HIV Basic Science, Vaccines, and Cure Project Blog
By Richard Jefferys, Project Director
Conference Catch Up: HIV Cure Research
11/19/19 - A number of conferences and workshops related to HIV cure research have taken place over the past several months, many of which can be viewed or learned about online. Links and some brief reports from four events are provided below. READ MORE
Case Report from the First Clinical Trial of CRISPR-Edited Stem Cells in People with HIV and Cancers
10/24/19 - One of the ways TAG keeps track of developments in HIV cure research is by maintaining an online listing of clinical research culled from trial registries (primarily clinicaltrials.gov). In May 2017, a research group in China registered the first human HIV trial involving the CRISPR/Cas9 gene editing system—a technology that has generated considerable excitement and attention due to promising results in small animal models. Last month in the New England Journal of Medicine, the researchers published a case report describing outcomes in a study participant (presumably the first individual enrolled). READ MORE
Tracing the Formation of the HIV Reservoir
10/22/19 - In a previous report from the AIDS 2018 conference in Amsterdam, I briefly covered a presentation by Sarah Joseph from the University of North Carolina suggesting that the bulk of the persistent, replication-competent HIV reservoir is formed around the time that antiretroviral therapy (ART) is initiated. Details of the study have now been published in Science Translational Medicine, and Joseph and colleagues have also outlined how the findings might be exploited therapeutically in a separate open access paper in Frontiers in Immunology. READ MORE
Distinguishing Potential Mechanisms of HIV Persistence
10/11/19 - For researchers attempting to develop a cure for HIV infection, it's important to understand the mechanisms by which the virus persists in the body despite suppression of viral load to undetectable levels by ART. Debate has centered around two possibilities that aren't necessarily exclusive:
- HIV continues to replicate at low levels in body tissues that ART drugs may not penetrate well (often referred to as sanctuary sites).
- Cells with HIV integrated into their genetic code—latently infected cells—persist and proliferate even though ART has shut down virus replication.
In recent years, evidence has accumulated indicating that, in most people who are adherent to ART, HIV replication is completely suppressed. A new report in the journal Science Advances adds to this evidence by analyzing individuals in receipt of long-term ART. The results support the increasing research focus on the persistence and proliferation of HIV-infected cells as the major obstacle to a cure, a topic addressed by several other recently published papers. READ MORE
Widely Publicized Report Associating the CCR5-Δ32 Mutation with Reduced Longevity is Retracted
10/9/19 - In June of this year, a short paper was published in the journal Nature Medicine reporting that individuals homozygous for the CCR5-∆32 mutation showed a 21% increase in the rate of all-cause mortality compared to those without the mutation (or heterozygotes, who inherit the mutation from one parent). The senior author, Rasmus Nielsen, stated to the Wall Street Journal that this would equate to a nearly two-year shortening of lifespan on average. The findings were the subject of hundreds of media articles, largely because they came on the heels of a misguided and completely unethical experiment in which the CCR5 gene was edited in two embryos, leading to the birth of genetically altered twins. Questions were also raised about possible relevance to HIV cure research studies that attempt to ablate CCR5 expression with gene therapies. Yesterday, Nature Medicine published a notice that the paper has been retracted. READ MORE
Selected Highlights from CROI 2019
4/10/19 - The 2019 Conference on Retroviruses and Opportunistic Infections (CROI) took place in Seattle from March 3rd-7th. The major news on the cure research front was the possibility of two additional cases similar to Timothy Ray Brown, who for the past 12 years has been the only individual considered cured of HIV infection (TAG issued a statement offering our perspective). Other notable reports included the first results from a study using CRISPR/Cas9 to target latent SIV in macaques and a novel insight into the source of residual viral load in people on ART. Immediately preceding the conference, TAG joined with multiple other organizations to co-sponsor the annual pre-CROI community HIV cure research workshop; slides and video from the event are available online. READ MORE
The Influence of Nef Protein Function on HIV Reservoir Size
1/15/19 - A paper published in the Journal of Virology on January 2nd reports that the nefarious activities of HIV's Nef protein can influence the size of the persistent viral reservoir in people on ART. Nef is known to be able to shield HIV-infected cells from recognition by the immune system, and Fredrick Omondi and colleagues found that this capacity correlated with measures of the HIV reservoir in a group of early-treated individuals assessed after 48 weeks of ART. The researchers also uncovered evidence that HIV reservoir size differed depending on viral subtype, likely partly due to between-subtype variation in the Nef protein. READ MORE
Significant Effects of a TLR7 Agonist Plus Broadly Neutralizing Antibody in the SHIV/Macaque Model
10/25/18 - Among the most newsworthy presentations at CROI 2018 earlier this year was Dan Barouch's description of a study involving a toll-like receptor 7 (TLR7) agonist combined with a broadly neutralizing antibody (bNAb) in SHIV-infected macaques (see contemporary coverage by AIDSMap, i-Base and POZ Magazine). The results have now been published in the journal Nature. READ MORE
Combining Broadly Neutralizing Antibodies Shows Promise
10/12/18 - At CROI 2017, Michel Nussenzweig from Rockefeller University presented evidence that early administration of a short course of two broadly neutralizing antibodies (bNAbs)—3BNC117 and 10-1074—led to prolonged immunological control of SHIV viral load in macaques. The study was subsequently published in Nature. At the end of last month, results from the first human trials of the same dual bNAb regimen were announced in papers in Nature and Nature Medicine. READ MORE
2018 NIAID Strategies for an HIV Cure Meeting
10/9/18 - The biannual National Institute of Allergy and Infectious Diseases (NIAID) Strategies for an HIV Cure Meeting kicks off tomorrow, October 10, at 8:30am US Eastern Time and continues until Friday at 12:30pm. The agenda is available online. For those unable to attend in person the entire event is being made available for viewing via the National Institutes of Health videocast website (see the upcoming events link).
Post-AIDS 2018 Updates on HIV Cure Research
9/19/18 - In the aftermath of the 22nd International AIDS Conference (AIDS 2018), which took place in Amsterdam in July, there has been some reflecting on the challenges facing the HIV cure research field. The presentations that garnered the most news coverage described disappointing study results, but there were also nuggets of novelty and encouragement to be found amidst the sea of data on offer (see previous post for links to relevant conference sessions, many of which now have video and/or slides available). READ MORE
Studying HIV Persistence in Liver Macrophages
9/12/18 - The major reservoir of HIV that persists despite ART is contained in long-lived memory CD4 T cells. Whether other cell types, particularly macrophages, can harbor a reservoir of replication-competent HIV—and thus contribute to viral load rebound if ART is interrupted—remains uncertain, and a matter of some controversy among scientists. The question is important, because identifying and eliminating virus reservoirs is a central plank of the research effort to cure HIV infection. In a new paper in the Journal of Clinical Investigation (available open access), Abraham J. Kandathil and colleagues investigate whether human liver macrophages—which they note comprise up to 90% of all tissue macrophages—can sequester infectious HIV in people on ART. READ MORE
HIV Cure-Related Research at AIDS 2018
7/19/18 - Workshops, sessions and presentations related to HIV cure research at the upcoming AIDS 2018 conference in Amsterdam.
Elite Controllers: Sex Differences and Factors Associated with Loss of Immune Control
3/14/18 - Over the past few months, several interesting papers addressing elite control of HIV infection have seen publication. The ability of elite controllers to maintain undetectable viral loads and relatively preserved CD4 T cell counts in the absence of ART has led them to be proposed as a model for a functional cure of HIV infection. But there is also evidence that many elite controllers exhibit elevated levels of inflammation compared to HIV-negative counterparts, and eventually experience disease progression, leading some researchers to call this proposition into question. The uncertain relevance of elite control to HIV cure research is prompting studies that attempt to parse the factors distinguishing individuals who preserve elite controller status from those who ultimately progress. READ MORE
Assessing Antiretroviral Therapy Interruptions in HIV Cure Research
2/22/18 - Last month, researchers from the Laboratory of Immunoregulation at the National Institute of Allergy and Infectious Diseases (NIAID) published a paper in PLoS Pathogens addressing the use of antiretroviral therapy (ART) interruptions in HIV cure research. The joint lead authors were Katherine E. Clarridge and Jana Blazkova, and the focus of the study was on the effects of an analytical treatment interruption (ATI) performed during a clinical trial of the broadly neutralizing antibody VRC01. The main results offer reassurance that the ATI had no long-term negative effects for participants—as articulated in an accompanying NIAID press release titled NIH Study Supports Use of Short-Term HIV Treatment Interruption in Clinical Trials—but there are some possible safety concerns that the data does not address. READ MORE
Recruiting Natural Killer Cells to Target HIV Persistence
1/18/18 - An important goal in HIV cure research is the identification of immune responses that might be induced or enhanced to promote clearance of virus-infected cells. The main focus of this work has been on adaptive immunity—components of the immune system that can specifically recognize HIV, which include CD4 T cells, CD8 T cells, B cells and antibodies. But there is growing interest in cells considered part of the innate immune system, particularly natural killer (NK) cells. NK cells have the potential to destroy virus-infected cells by several mechanisms, including the identification of generic signs of cellular distress or infection, or via antibody-mediated recruitment to a target cell (known as antibody-dependent cellular cytotoxicity/ADCC). READ MORE
New Data on Identifying and Targeting the Latent HIV Reservoir
1/17/18 - Several recently presented and published studies offer potentially important new data relevant to efforts to identify cells containing latent HIV and target them for elimination. READ MORE
Update on AAV Vectors as Delivery Vehicles for Broadly Neutralizing Antibodies: Ron Desrosiers and the Miami Macaque
12/14/17 - The idea of using adeno-associated virus (AAV) as a vehicle to deliver genes encoding anti-HIV broadly neutralizing antibodies (bNAbs) has been around for some time, and has been covered a number of times previously on the blog (e.g. see posts from May 2009 and January 2013). The approach was first developed by Phil Johnson as a possible way of circumventing the challenges associated with inducing broadly neutralizing antibodies using traditional vaccines. AAVs primarily take up residence in muscle tissue and can act as a factory for producing proteins encoded by genes inserted into the AAV genome. This past Tuesday evening at the HIV Persistence Workshop in Miami, the researcher Ron Desrosiers presented an update on efforts to deliver bNAbs with AAV, including the intriguing tale of a macaque in which the method appeared to have a profound therapeutic effect. READ MORE
Additional Remission Cases Published
12/5/17 - Two recent case reports of temporary HIV remission, first presented at this year's CROI and IAS conferences, have now been published in the open access journal PLoS Medicine. READ MORE
HIV Latency: Trapped in Transition, Lurking in Treg
11/16/17 - The question of how HIV latency is typically established in long-lived memory CD4 T cells has yet to be fully resolved. One theory is that latency occurs when HIV infects a CD4 T cell that is in the process of transitioning from an activated state to a resting state, but direct evidence has been lacking. A new paper from the research group of Robert Siliciano, published in the journal Immunity, provides experimental support for this model of HIV latency initiation. READ MORE
Locking Down Latent HIV
11/2/17 - Strategies for dealing with the reservoir of latent HIV that persists despite antiretroviral therapy (ART) have primarily focused on awakening the virus from its dormant state. But Susana Valente and colleagues from the Scripps Research Institute in Florida are taking a different tack, flipping the idea of latency reversal on its head. Their approach—which they have dubbed block and lock—involves trying to imprison latent HIV in a way that prevents it from ever reactivating. The latest work by Valente's group was published recently in the open access journal Cell Reports. READ MORE
Estimating the Total Size of the HIV Reservoir
10/30/17 - A paper published earlier this month in Nature Medicine by Jake Estes and colleagues addresses the difficult challenge of attempting to define the distribution and total size of the persistent HIV reservoir. The researchers employed a variety of tests to measure viral RNA and DNA—including new imaging techniques they have developed named RNAscope and DNAscope—in multiple tissues from untreated or ART-treated macaques (infected with SIVmac251, SIVmac239 or SHIV) as well as lymph node and rectal tissue samples from a cohort of 20 individuals on ART in Kampala, Uganda. READ MORE
Effects of the Anti-Inflammatory Antibody Canakinumab on Heart Disease and Cancer: Implications for HIV?
10/12/17 - Inflammation is increasingly recognized as an immunological double-edged sword: it contributes importantly to the response to infection, but can also cause serious collateral damage to the body—particularly when persistent—and has been implicated as potentially contributing to multiple conditions, including heart disease and cancers. Researchers have found that the anti-inflammatory effects of statin drugs contribute to their beneficial effects against cardiovascular disease, but because statins also reduce cholesterol it has not been possible to disentangle the relative importance of these two potential mechanisms of action. READ MORE
2017 IAS HIV Cure & Cancer Forum
9/29/17 - The IAS HIV Cure & Cancer Forum was held at the renowned cancer research center Institut Curie in Paris on July 22 & 23 of this year. A report from the meeting, authored by Genevieve E. Martin, José Alcami, Jean-Phillipe Spano and Anna Laura Ross, has just been published in the open access Journal of Virus Eradication, and many of the slide presentations are posted to the Forum website. READ MORE
Mosaic Antigens and Mountaineering Metaphors: Climbing Toward the Next HIV Vaccine Efficacy Trial
8/25/17 - The pharmaceutical industry has made significant contributions to HIV vaccine research, but it has been rare for a major company to take the leading role in propelling a candidate toward efficacy testing. The only example to date occurred around the turn of the millennium with Merck's adenovirus serotype 5 (Ad5) vector, which showed some evidence of promise in macaque models but was ultimately discontinued after being associated with an enhanced—rather than reduced—risk of HIV acquisition in the STEP and Phambili trials. READ MORE
HIV Remission News from IAS 2017
7/25/17 - The 9th International AIDS Society Conference on HIV Science (IAS 2017) began on Sunday in Paris, and the topic of HIV remission has been the focus of several high profile presentations. READ MORE
Evidence of Smaller HIV Reservoirs in a Ugandan Cohort
6/12/17 - The size of the reservoir of replication-competent HIV that persists in individuals on ART has been described in several studies from North America, but no information has previously been presented from the African continent, where the burden of HIV infection is greatest. A study just published in Clinical Infectious Diseases by Jessica Prodger and colleagues takes a first step toward filling this gap, and the results may be surprising. READ MORE
Flagging the HIV Reservoir
3/16/17 - The rarity of CD4 T cells containing latent HIV in people on antiretroviral therapy—the typical estimate is around one per million CD4 T cells—makes them extremely challenging both to study and target with therapies. A paper published online yesterday in Nature represents a possible breakthrough in this area, reporting that it may be possible to identify many latently infected CD4 T cells due to expression of a particular cell surface protein, CD32a. READ MORE
Capsules From CROI 2017
3/10/17 - The annual Conference on Retroviruses & Opportunistic Infections (CROI) took place in Seattle from February 13th-16th, offering a dizzying parade of new data. Webcasts of presentations and PDF files of posters were rapidly placed online and are accessible via the CROI website. READ MORE
Targeting Latently Infected Cells via IFITM1
1/23/17 - One of the holy grails in cure research is the discovery of markers that would allow the specific targeting of cells harboring latent HIV. The goal is to be able flag those cells for elimination while sparing their uninfected counterparts. So far, a number of cellular receptors have been identified as being more commonly—but not exclusively— expressed on latently infected cells, such as PD-1, LAG-3 and TIGIT. In the new issue of the open access journal JCI Insight, Rui André Saraiva Raposo and colleagues from the laboratory of Doug Nixon at The George Washington University add a new candidate to the mix: interferon-induced transmembrane protein 1 (IFITM1). READ MORE
Therapeutic Vaccination Plus Toll-Like Receptor Stimulation Shows Promise in the SIV Model
12/16/16 - Since the earliest days of HIV research, the idea of trying to enhance immune responses to the virus using therapeutic vaccination has been extensively explored, but with little success. The ability of the virus to compromise CD4 T cells, which would normally coordinate antiviral immunity, may be one contributor to the generally disappointing results. Virus-induced damage to the lymph node environment where immune responses are initiated has also been suggested to play a role. Researchers have not given up, however, and a recent study in SIV-infected macaques has produced encouraging results. READ MORE
Applying the Brakes to Type 1 Interferons in HIV Infection
12/15/16 - This week in the Journal of Clinical Investigation, two independent studies describe results obtained by blocking type 1 interferon signaling pathways in humanized mouse models of chronic HIV infection. The papers are both open access (see Anjie Zhen et al and Liang Cheng et al). Type 1 interferons are cytokines that interact with specific receptors on cells in order to modulate activity of interferon-stimulated genes (ISGs), and these interactions are known to play important roles in antiviral immunity (e.g. alpha interferon is an approved treatment for hepatitis C). But the effects of type 1 interferons are complex, and can also involve potentially harmful exacerbation of immune activation and inflammation. In these new studies, the researchers used antibodies to block interferon receptors in humanized mice with chronic HIV infection, and converged on congruent findings: HIV viral loads and virus reservoirs were diminished, as were markers of immune activation and exhaustion. READ MORE
NIAID Strategies for an HIV Cure Workshop
11/11/16 - Next week from Monday through Wednesday the National Institute of Allergy and Infectious Diseases (NIAID) is convening their third scientific workshop on HIV cure research, Strategies for an HIV Cure 2016. The meeting will be held in the Ruth Kirschstein Auditorium at the Natcher Conference Center (Building 45) on the National Institutes of Health Main Campus. For the first time, the proceedings will be available for public viewing via live webcast at: https://videocast.nih.gov. A detailed agenda is available online. A room has been made available for the use of community advocates attending the workshop in person: Natcher room G1/G2 on the lower level of the conference center.
Antibody Therapy Leads to Sustained Post-Treatment SIV Control in Macaques
10/17/16 - A study published last Thursday in the journal Science has hit the headlines, reporting that sustained post-treatment control of SIV has been achieved in macaques using an antibody therapy developed for the treatment of inflammatory gastrointestinal (GI) disorders. The antibody targets α4β7, a receptor expressed on CD4 T cells (and other immune system cells) that is involved in promoting trafficking to the GI tract. Some, but not all, studies have suggested that α4β7 also plays a role in mediating HIV infection of target CD4 T cells. READ MORE
HIV Persistence: Defective Virus Copies Accumulate Rapidly After Infection
9/14/16 - A major challenge in measuring the reservoir of HIV that persists despite antiretroviral therapy (ART) is that many of the virus genomes that can be found integrated into the DNA of CD4 T cells are incomplete or mutated in ways that preclude further rounds of replication. For researchers aiming to develop a cure, it is important to try and distinguish between defective virus copies and intact viruses capable of rekindling the infection when ART is interrupted. A new study from the laboratory of Robert Siliciano, published in the latest issue of Nature Medicine, attempts to assess the proportions of defective and replication competent HIV in people on ART, comparing individuals who began treatment very early after infection to those who started later. READ MORE
Probiotic-Based Vaccine Candidate Fails in Independent Study
5/20/16 - Back in 2012, a paper describing a study of a novel vaccine approach in the SIV/macaque model was published to little fanfare in the open access journal Cell Reports. The brainchild of researcher Jean-Marie Andrieu, the idea behind the vaccine was to turn the traditional approach to immunization on its head: the aim was to suppress the response to SIV, thereby depriving the virus of the activated CD4 T cell targets that normally fuel viral replication. A probiotic, Lactobacillus plantarum, was used to deliver SIV antigens to the gut with the goal of inducing SIV-specific immune tolerance. Macaques were then challenged with pathogenic SIV. The results were surprising and unprecedented: 15 out of 16 animals resisted infection. Protection was associated with the induction of SIV-specific CD8 T cells displaying a regulatory, immune-suppressive phenotype. READ MORE
Long-Awaited HIV Vaccine Efficacy Trial Gets the Green Light
5/18/16 - In 2009, a slight but statistically significant level of protective efficacy was reported from a large HIV vaccine trial conducted in Thailand. The trial, named RV144, involved a combination of an ALVAC canarypox vector encoding HIV antigens and a gp120 protein boost (AIDSVAX). Receipt of the vaccines was associated with a 31.2% reduction in the risk of HIV acquisition in a community sample of 16,402 adults aged between 18 and 30; the results were published in the New England Journal of Medicine. Ever since that time, plans have been afoot to assess whether the results can be duplicated or improved upon in other settings, and today the National Institute of Allergy and Infectious Diseases (NIAID) announced that a new efficacy trial is going to be launched in South Africa later this year. READ MORE
Snipping the HIV Genome Out of Latently Infected Cells
3/23/16 - One of the more futuristic-sounding ideas for curing HIV infection involves trying to remove the genome of the virus from the genome of the cells into which it has integrated. On paper, the idea is very appealing, but there are a multitude of challenges associated with trying to identify integrated HIV DNA (referred to as proviral DNA or provirus) and then excise it from the DNA of an infected cell without causing untoward effects. In 2014, the research group of Kamel Khalili at Temple University in Philadelphia drew extensive news coverage when they reported some success in laboratory experiments; this work and the media response were covered at the time on TAG's media monitor page. Khalili and colleagues have now published a new paper and again have generated considerable press (in broad terms, TAG's previous commentary on interpreting the research and associated stories remains relevant). In addition to Khalili's new findings, another paper has been published recently that describes a slightly different approach toward excising HIV DNA, also reporting encouraging results but similarly limited to the laboratory setting. READ MORE
Cure Research News from CROI 2016
3/10/16 - The 2016 Conference on Retroviruses and Opportunistic Infections (CROI) took place in Boston from February 22-25. CROI deserves kudos for pioneering comprehensive webcasting, and all sessions are available for viewing online. Results from several significant cure-related clinical trials were debuted during the meeting (links to the webcasts are in parentheses): READ MORE
New Paper Rekindles Debate on HIV Replication During ART
2/4/16 - For many years scientists have probed the question of whether combination antiretroviral therapy (ART) completely inhibits all HIV replication in the body. The preponderance of evidence has suggested that it does, and opinion has generally tilted toward the idea that persistent virus replication in the face of ART is relatively uncommon. The evidence includes studies of ART intensification (adding multiple drugs to standard combinations), which in most—but not all—cases have documented no effect on levels of residual HIV, as well as genetic studies showing a lack of viral evolution over time in people on long-term treatment. The question remains controversial, however, and some scientists continue to believe that low-level ongoing HIV replication on ART may occur in hard-to-access sites in the body. READ MORE
HIV Cure Research Reviews in the Journal of Clinical Investigation
2/4/16 - The Journal of Clinical Investigation has published a collection of reviews on HIV cure research edited by Robert Siliciano. The articles are not open access unfortunately, but a day pass for the journal's website (which allows downloading of all PDFs) costs $10 which is relatively affordable compared to many other publishers. READ MORE
New Data on the Latency-Reversing Activity of Disulfiram
12/1/15 - Several years ago, the laboratory of Robert Siliciano at Johns Hopkins University reported that the FDA-approved drug disulfiram (Antabuse) could reverse HIV latency in laboratory experiments. The discovery led Steve Deeks and colleagues to conduct a small pilot study in HIV-positive people on ART, which found that a standard dose of 500mg/day of disulfiram showed some hints of latency-reversing activity that appeared to be linked to whether drug levels were detectable in blood. In turn, the pilot study spurred the launch of a larger clinical trial investigating the effects of higher disulfiram doses (up to 2000mg/day) in a cohort of 30 HIV-positive individuals on ART. Results from this trial have now been published in The Lancet HIV. READ MORE
Developing Multi-Pronged Antibodies to Target the HIV Reservoir
11/11/15 - In an example of publication kismet, three recent open access articles all converge in describing a new strategy for depleting the HIV reservoir. The research involves engineering antibodies or antibody-like molecules capable of simultaneously binding two targets: the CD3 receptor, a human protein expressed on T cells, and parts of the HIV envelope (Env) protein, which are typically displayed on the outside of infected CD4 T cells when the virus is active. The rationale is that the region of the antibody that targets HIV Env binds to infected cells, while the CD3-targeting region binds to passing T cells and activates them to kill the cell. The idea for this two-pronged—termed bispecific—antibody attack originated in cancer research, and one candidate that targets CD19 (a protein expressed by B cells) and CD3 is already FDA-approved as a second-line treatment for certain forms of acute lymphoblastic leukemia. READ MORE
T-Cell Exhaustion Biomarkers Linked to Time to Viral Load Rebound in the SPARTAC Trial
11/11/15 - A study published in Nature Communications has drawn a fair amount of press coverage—and some hyperbolic headlines—by reporting that certain immunological biomarkers may be able to predict the likelihood of maintaining a low viral load after an antiretroviral therapy (ART) interruption. READ MORE
A Trio of Papers Provide New Insights Into Host Cell Manipulation by HIV
10/6/15 - Viruses are notorious for manipulating host cells in ways that favor viral replication, and HIV is no exception. The HIV protein Nef has a well-described capacity to subvert normal cellular biology, including down-regulating cell surface class I HLA molecules that might otherwise allow CD8 T cells to recognize that the cell is infected. Last week saw the publication of three independent studies that all report the discovery of another important Nef function. READ MORE
SMAC Mimetics and HIV Latency
10/6/15 - SMAC (Second Mitochondrial-derived Activator of Caspases) mimetics are a class of compounds that have recently entered clinical trials as potential cancer treatments. The drugs antagonize anti-apoptotic proteins, thereby promoting the apoptotic death of cancer cells. Earlier this year at CROI, a poster presentation offered evidence that SMAC mimetics may also selectively promote the apoptosis of CD4 T cells latently infected by HIV. In a new open access paper published by Cell Host & Microbe, Lars Pache and colleagues add another string to SMAC mimetics bow, reporting that the drugs can work synergistically with HDAC inhibitors to reverse HIV latency. In an experiment using resting CD4 T cells sampled from individuals on suppressive ART, the combination of the SMAC mimetic SBI-0637142 and the HDAC inhibitor panobinostat activated latent HIV as efficiently as T cell activation. Preliminary results from a phase I cancer trial suggest that the SMAC mimetic birinapant has an acceptable toxicity profile for testing in humans, potentially opening the door for studies of these compounds in HIV. READ MORE
Attempt to Oversell New Findings on Pyroptosis in HIV Infection Prompts Headline Debacle
8/28/15 - A new open access paper from the laboratory of Warner Greene at the Gladstone Institutes was published online yesterday in the journal Cell Reports, accompanied by a poorly conceived press release that prompted some of the most egregiously inaccurate media headlines about HIV research in recent history. READ MORE
Combining PKC Agonists and Bromodomain Inhibitors to Reverse HIV Latency
8/14/15 - Two recent papers in PLoS Pathogens report that combinations of candidate latency-reversing agents can potently activate HIV production by latently infected CD4 T cells in laboratory experiments. Pairings of the PKC agonists Bryostatin-1 or ingenol with the bromodomain inhibitor JQ1 were most effective, generating levels of virus production by latently infected cells similar to those achieved by maximal T cell activation. The results appear consistent with those published earlier this year by the research group of Robert Siliciano at Johns Hopkins University, and are encouraging because there had been some skepticism as to whether any latency reversing strategy could match the effects of maximal T cell activation (which is known to be too dangerous to use in people). But there are caveats: the compounds do affect T cell activation pathways and it is not yet known if they will be safe in HIV-positive individuals; currently, they are being tested (and in the case of ingenol, used topically) as cancer treatments. READ MORE
Estimating How Frequently Latent HIV Reactivates
8/7/15 - The primary barrier to curing HIV infection is the persistence of the virus in a latent form in long-lived resting memory CD4 T cells. The number of latently infected resting memory CD4 T cells in a typical individual on ART is estimated to be in the range of 1-60 million. An important strand of HIV cure research involves attempting to reduce the size of this persistent HIV reservoir, in hopes of delaying or—better yet—preventing viral load rebound when ART is interrupted. In order to gain insight into how feasible this might be, researchers have employed mathematical modeling to estimate how the size of the HIV reservoir relates to time to viral load rebound. READ MORE
Innate Immunity and HIV DNA Declines in Panobinostat Recipients
8/4/15 - Results from a phase I trial of the candidate latency reversing agent panobinostat were published last year in The Lancet HIV (see blog post from November 2014). The paper notes that in an exploratory analysis, a subset of four (out of a total of 15) participants experienced a significant decline in cell-associated HIV DNA levels of around 70-80%, although there was no detectable change in the trial cohort overall. Furthermore, the HIV DNA reduction in these four individuals was associated with a slightly longer time to viral load rebound during an analytical ART interruption. At the NIAID-sponsored Strategies for an HIV Cure meeting in October 2014, Matthias Lichterfeld reported that several measures of innate immunity correlated with the observed diminution of HIV DNA, and these analyses have now been published online in the Journal of Virology. READ MORE
News and Notes from IAS 2015
7/31/15 - Last week saw a slew of news emerge from the IAS 2015 conference and related satellite meetings in Vancouver. Below are links to some presentations of possible interest and information on how to find materials online. READ MORE
New Case of "Remission" Reported in a Perinatally Infected Teenager
7/23/15 - A new example of long-term post-treatment control of HIV viral load was reported on Monday at the 8th IAS Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2015) in Vancouver, attracting widespread media attention. Presented by Asier Sáez-Cirión from Institut Pasteur in France, the case involves a teenager who acquired HIV infection perinatally and was taken off ART at around the age of six, subsequently maintaining very strict control of viral load for over 12 years and counting. Sáez-Cirión is also the lead investigator for the well publicized VISCONTI cohort, a group of early-treated adults who are exhibiting long-term of HIV viral load after ART interruption (described in some detail in a paper in 2013, at which time the cohort had 14 members, and recently reported to now number 20 with an average time off ART of over nine years. Update 7/25/15: this information on the VISCONTI cohort appears to no longer be true, see addendum below). ). READ MORE
Interleukin-21 May Have Therapeutic Potential in HIV Infection
7/15/15 - Cytokines are a family of proteins that play important roles in immune cell communication. The best-known example is interleukin-2 (IL-2), which is FDA-approved as a therapy for kidney cancer. Many cytokines have been evaluated in HIV infection and one of the latest candidates being considered for human testing is IL-21. Laboratory and animal model research indicates IL-21 can enhance natural killer cell and CD8 T cell activity, and clinical trials are already underway in people with cancers. READ MORE
Prime-Boost HIV Vaccine Approach Shows Promise in Macaques; Janssen Aims to Advance to Human Efficacy Trials
7/14/15 - A paper published earlier this month in Science augurs a major new effort to advance a prime-boost HIV vaccine strategy into human efficacy trials. The vaccine components are manufactured by Crucell Holland B.V, which is now one of the Janssen Pharmaceutical Companies of Johnson & Johnson, and—in a very welcome development for the HIV vaccine field—Janssen has recently outlined a comprehensive development plan that they hope will lead to a licensable HIV vaccine. Frank Tomaka, MD, Clinical Leader, HIV Vaccines presented details on an AVAC webinar held May 18th (slides and audio are available online). Since the failure of Merck's candidate in 2007, there has been a dearth of major pharmaceutical company involvement in HIV vaccine research, and planning for further efficacy trials was limited to one collaborative endeavor known as the Pox-Protein Public-Private Partnership (P5) (the work of P5 is also described on the AVAC webinar by Glenda Gray). The promising macaque results described in the new Science paper offer some insight into why Janssen has now entered the fray. READ MORE
Perspectives on Post-Treatment Control of HIV
5/22/15 - Several recent papers offer perspectives on the possibility of achieving post-treatment control of HIV replication by starting antiretroviral therapy (ART) during acute infection. Interest in this topic has been sharpened by reports about the VISCONTI cohort, a group of individuals in France who all started ART soon after HIV acquisition, maintained treatment for several years, then interrupted and are now controlling viral load to very low or undetectable levels. At the time of the last published update, the VISCONTI cohort included 20 individuals (identified from various trials) who have been off ART for an average of nine years. READ MORE
Enlisting Mice in the Search for Residual HIV
5/4/15 - One of the challenges in HIV cure research is developing methods for finding extremely low levels of replication-competent virus. For example, there have been three cases where individuals were considered possibly cured of HIV because the virus could not be detected even though ART had been stopped (the Mississippi baby and two Boston patients), but all ultimately experienced viral load rebounds. The research group of Joel Blankson at Johns Hopkins University is working on an approach to this problem involving mice, and recently published preliminary results in the Journal of Infectious Diseases. READ MORE
Mapping the HIV Integration Landscape: "Cancer Genes" and the Persistence of the Latent Reservoir
4/24/15 - Several presentations at last year's CROI offered evidence that the proliferation and persistence of latently infected CD4 T cells is associated with HIV integration into certain genes that have also been implicated in the development of cancers. The results prompted the investigators to hypothesize that HIV integration into cancer-associated genes plays a causative role in sustaining the reservoir of latently infected CD4 T cells by promoting their survival. Some of the scientists involved in the research went so far as to suggest that the findings might somehow contribute to explaining the elevated risk of cancer in HIV-positive people (see the CROI 2014 summary on the blog). The studies were eventually published in Science last July, along with a commentary by David Margolis and Frederic Bushman pointing out that "most HIV-related malignancies are not T cell cancers, and even most HIV-related lymphomas are of B cell origin" and gently noting: "alternative interpretations of the data are possible." READ MORE
Combining Latency-Reversing Agents, and Reviewing Methods of Measuring the Latent HIV Reservoir
4/16/15 - At CROI last year, Gregory Laird presented results from a laboratory study that tested the activity of several candidate HIV latency-reversing agents (LRAs) on latently infected CD4 T cells isolated from HIV-positive individuals on ART. The results were disappointing: only one LRA showed a very modest effect on HIV gene expression and none induced significant production of HIV virions (the study was later published in Nature Medicine). Laird concluded his CROI talk by offering a glimpse at more hopeful preliminary data suggesting that combinations of LRAs could perform better, and these experiments have since been completed and were published recently in the Journal of Clinical Investigation (the paper is open access). READ MORE
Broadly Neutralizing Antibody Suppresses HIV in Clinical Trial
4/9/15 - The past decade has seen a boom in the identification of antibodies capable of potently neutralizing a broad array of different HIV isolates (broadly neutralizing antibodies or bNAbs). New technologies that allow antibodies to be fished from huge numbers of individual B cells and tested for activity have spurred this rapid acceleration of discovery. There is now intense interest in learning whether the blossoming array of bNAbs can be put to therapeutic and preventive use. A paper published yesterday in Nature describes encouraging results from a phase I trial involving the bNAb 3BNC117. Reflecting the level of interest in the topic, the paper has attracted extensive press coverage. READ MORE
Souped-Up IL-15 Sparks Natural Killer Cell Activity Against HIV
4/9/15 - The cytokine interleukin-15 (IL-15) can exert a range of effects on the immune system, but is particularly important for promoting the proliferation and function of natural killer (NK) cells and CD8 T cells. Some observational studies in HIV have suggested salutary effects of higher IL-15 levels, in one case finding an association with delayed viral load rebound after ART interruption. But attempts at therapeutic administration of the cytokine to SIV-infected macaques have generally produced deleterious effects, including CD4 T cell depletion. More recently, IL-15 has been reexamined in the context of cure research, with laboratory studies demonstrating it can induce latently infected CD4 T cells to produce HIV. There is also increasing interest in therapeutic manipulation of NK cell responses as a means to eliminate the HIV reservoir, a task for which IL-15 may be well suited. A paper published last week in the Journal of Virology reports that an optimized form of IL-15 promoted potent inhibition of HIV by NK cells in humanized mice. READ MORE
CROI 2015 Round Up
3/18/15 - The 2015 Conference on Retroviruses and Opportunistic Infections (CROI) took place in Seattle from February 23rd to the 26th. The major news that emerged from the meeting was the extremely high degree of protection from HIV infection obtained with pre-exposure prophylaxis in two studies, PROUD and IPERGAY. On the vaccine and cure fronts nothing was quite as headline grabbing, but there were a number of interesting presentations. Webcasts of all conference sessions are available on the CROI website along with the abstract book and, where available, PDFs of posters. Excellent coverage of CROI is available from several websites, including AIDSMap, i-Base and NATAP (whose reports often include slides from the talks). READ MORE
Novel, Broadly Active HIV Inhibitor Shows Potential
2/19/15 - A paper published yesterday in Nature has stirred considerable excitement and widespread media coverage. Led by the laboratory of Michael Farzan at The Scripps Research Institute, the research involves a newly designed inhibitor of HIV named eCD4-Ig. The inhibitor is designed to bind the HIV envelope at sites that attach to CD4 and CCR5 molecules on CD4 T cells; blocking this interaction prevents HIV from gaining entry and infecting the cell. In laboratory experiments, eCD4-Ig showed activity against an unprecedentedly broad array of HIV and SIV variants, including viruses known to be resistant to even potent neutralizing antibodies. In addition to the greater breadth, activity was generally achieved at lower concentrations than has been documented with the broadly neutralizing antibodies (bNAbs) described to date. Due to similarities between HIV envelope binding to CCR5 and CXCR4 co-receptors, eCD4-Ig also proved capable of neutralizing CXCR4-dependent virus isolates. These results prompted the researchers to explore the preventive potential of eCD4-Ig in the rhesus macaque model, and it is the outcome of this part of the study that has particularly spurred the publicity. READ MORE
Report of "Aggressive" HIV Variant in Cuba
2/18/15 - On January 28th, a paper reporting evidence of rapid progression associated with a recently identified HIV-1 recombinant circulating in Cuba (CRF19_cpx) was published online by the journal EBioMedicine. CRF stands for circulating recombinant form, and CRF19_cpx represents a combination of HIV-1 subtypes A, D and G. Last week, the authors issued a press release about the study, and since then media coverage has gradually ballooned. Most of the coverage takes its lead from the press release headline: "An aggressive form of HIV uncovered in Cuba." The immediate problem is that the data are very preliminary, and it is way too soon to declare—as fact—that what has been uncovered is "an aggressive form of HIV." It may or may not be, additional evidence is needed in order to make that determination. Many media stories also state that HIV CRF19_cpx causes AIDS within three years, which is potentially very misleading because what the study reports is that this rapid pace of progression occurred in a total of nine untreated people who were found to be infected with the strain; this does not prove that all people infected with HIV CRF19_cpx will progress at this rate. There is no evidence to suggest that HIV CRF19_cpx would not respond to treatment. READ MORE
Lymphoid Tissue Fibrosis: New Studies and Candidate Therapies
1/30/15 - Research has documented that HIV infection is associated with significantly increased scarring damage to lymphoid tissue, termed fibrosis. Fibrosis can be quantified by measuring the deposition of collagen, and the amount of lymphoid tissue fibrosis in HIV-positive people has been shown to correlate directly with CD4 T cell depletion. A paper published toward the end of last year by Timothy Schacker's group at the University of Minnesota describes results of an analysis of gut-associated lymphoid tissue (GALT) fibrosis in untreated HIV controllers and HIV-positive people on ART, compared to HIV-negative controls and the one person considered cured of HIV, Timothy Brown. The study was previously presented in part at CROI 2013. READ MORE
Latency-Reversing and Immunomodulatory Activities of HDAC Inhibitors
12/5/14 - Results from the second clinical trial to test the HDAC inhibitor vorinostat as a latency-reversing agent, first presented at CROI 2013, have now been published in the open access journal PLoS Pathogens. The study design differed from the first trial, involving a longer 14-day dosing period. The results are broadly consistent, with a significant increase in cell-associated HIV RNA documented, but no change in multiple measures of the HIV reservoir or HIV RNA as assessed by the standard viral load test. Side effects experienced by participants were grade 1 or 2 (mild or moderate in severity) with lethargy, diarrhea and thrombocytopenia being most common; all resolved after the drug was stopped. The researchers noted long-term changes in expression of multiple cellular genes and caution that this could present a safety concern, stating: "the prolonged changes in host gene expression require careful long term follow up." READ MORE
Is HIV Weakening Over Time?
12/2/14 - A little over nine years ago I wrote a blog post with this same title, about a widely publicized paper claiming that HIV had become less virulent. Although it's grim to be in the position of pouring cold water on optimistic-sounding scenarios, that paper was based on measuring HIV's ability to replicate using a laboratory test, and other published data raised questions as to whether the test could actually predict differences in disease progression rates. Today, it's déjà vu all over again because there has been an explosion of very similar media stories positing that HIV is evolving into a "milder form." And once again, the study prompting the coverage relies primarily on laboratory measurements of HIV replication capacity, despite the fact that a prior publication—by several of the same authors—reports that results from this test do not predict the rate of CD4 T cell decline over time. READ MORE
TAG HIV Cure Research Media Monitor
11/26/14 - In recent months, Treatment Action Group has created a web page resource that will attempt to provide accurate information on HIV cure research news that makes a splash in the mainstream media, particularly those stories that get mangled in the translation or are possibly based on dubious scientific claims. READ MORE
Update on Early HIV Treatment in Infants: IMPAACT Trial Launched, Additional Case Reports Published
11/26/14 - On November 3rd, the National Institute of Allergy and Infectious Diseases (NIAID) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) announced the launch of the IMPAACT P1115 trial, which will investigate very early initiation of HIV treatment in newborns. Much of the impetus for the trial came from the Mississippi baby case, and although that has turned out to involve an extended, 27-month remission from HIV replication rather than a cure, there remains a rationale for evaluating the feasibility, benefits and risks of early treatment in perinatal HIV infection. READ MORE
Three Papers on Macrophages and HIV Infection
11/25/14 - The question of whether HIV infection of macrophages plays an important role in pathogenesis remains controversial and unresolved. For cure researchers, the related question of whether macrophages contribute to viral persistence during antiretroviral therapy is crucial, but also unanswered. Three recent papers describe results from studies designed to shed light on this subject. READ MORE
HIV Reservoir Measurements and Viral Load Rebound after ART Interruption
11/18/14 - To assist in the search for therapies that might contribute to curing HIV infection, scientists are seeking to identify biomarkers that are associated with control of viral load after an antiretroviral therapy (ART) interruption. If reliable predictors of viral load control could be identified, the effect of candidate therapies on these biomarkers could be evaluated without necessarily having to ask clinical trial participants to undergo ART interruptions (which can pose risks to health). Two recent papers report that certain measurements of the HIV reservoir show statistically significant associations with viral load rebound, although the results are not entirely consistent. READ MORE
Panobinostat as a Latency-Reversing Agent: Phase I Trial Results Published
11/6/14 - In the spring of 2013, a wildly inaccurate Daily Telegraph story about HIV cure research claiming "there will be a breakthrough in finding a cure for HIV within months" was amplified around the Internet, understandably receiving a massive amount of attention and interest. To their credit, the researchers whose work prompted the piece published a statement addressing the inaccuracies, and eventually the Telegraph made extensive corrections. Recently, in the debut issue of The Lancet's new online HIV journal, results from the trial at the center of the story were published - to no fanfare whatsoever. READ MORE
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
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
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:
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
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
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
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
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
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
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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LONDON (Reuters) - Britain's Barclays (BARC.L) reined in its ambitions to be a Wall Street powerhouse on Thursday and signaled a return to its retail roots with a plan to hive off much of its investment bank and ax one in four jobs at the division.
Chief Executive Antony Jenkins, in his second strategic review in as many years, will cut 19,000 jobs in the next three years, 7,000 of them at the investment bank, and park 400 billion pounds of assets in a new "bad bank".
A slide in trading revenue due to investor uncertainty and tough post-crisis regulation combined with a string of senior staff departures and a row with shareholders over bonuses have forced Jenkins to take a knife to the investment bank, built up under predecessor Bob Diamond and once the firm's profit engine.
Jenkins said the recent halt in the trading boom was not just a cyclical ebb but was partly permanent, as regulators have tightened the screws on large banks in the past 12 months, making some trading activities too costly to pursue.
"We will refocus and resize our investment bank to bring balance to Barclays," he told analysts and investors. "As currently constituted, it is an unacceptable drag."
Barclays will park some 90 billion euros worth of risk-weighted assets from the investment bank in the bad bank, including some commodities and emerging markets products and some of its derivatives book.
The move echoes UBS, which in 2012 decided to exit the riskiest fixed-income trading areas and set up a non-core division to house around 90 billion Swiss francs of mainly investment banking risk-weighted assets. Since the creation of its in-house bad bank, UBS's shares have risen nearly 40 percent.
Barclays' investment bank will be left with 120 billion euros of risk-weighted assets and, while significantly smaller than U.S. players such as JP Morgan (JPM.N), will still be the largest investment bank in Europe with more assets than the "core" businesses of Deutsche Bank (DBKGn.DE) and Credit Suisse CSGN.VX after they also streamlined their operations.
Barclays bought the flagship U.S. brokerage arm of Lehman Brothers when the investment bank collapsed in 2008. Although there were some job losses during the integration into Barclays, the move brought thousands of former Lehman employees into the Barclays Capital business, many at a senior level within the combined firm.
Barclays shares were the top gainer in Britain's FTSE 100 index .FTSE and an index of European banking stocks .SX7P, leaping more than 7 percent to a near three-month high of 261.20 pence as investors digested the bank's pledge to boost shareholder returns with its more simplified business.
Barclays kept a targeted dividend pay-out ratio of 40 to 50 percent of net profit and is aiming to deliver a return on equity (RoE) in its core business of over 12 percent. Its RoE was just 4.5 percent last year.
Not all investors were impressed, however.
"When you're dealing with Barclays, it's very much a work in progress," said Ed Shing, global equity portfolio manager at BCS Asset Management, who does not hold Barclays in his fund.
"I think they'll concentrate more on equities but the problem is you'll see a lot of revenue shortfall in the other areas as they go through the necessary pruning and withdrawal from the Bob Diamond empire. And I think that's a lot of disruption still in the pipe."
Despite Thursday's share jump, Barclays is the third worst performing banking stock in Europe after HSBC (HSBA.L) and Deutsche Bank (DBKGn.DE), down over 10 percent so far this year.
Barclays' investment bank will concentrate on its core markets of the United States and the UK and the top 1,000 clients who generated more than three quarters of revenue last year.
The carve-up means the investment bank will account for no more than 30 percent of Barclays' risk-weighted assets, down from half now. It gives greater prominence to Barclays' retail operations in Britain, its Barclaycard credit card arm and its African business.
Jenkins is also parking all of Barclays' European retail banking operations in Italy, France, Spain and Portugal, and some corporate and Barclaycard assets in the bad bank. He said parts of the European operations could be sold or floated.
Outside of the investment bank, around half of the job cuts will be from branches in UK, Europe and Africa with most of the remainder slashed from operations and IT.
Jenkins, the former head of Barclays' retail business, has set out to turn the group around since taking over as CEO in August 2012 when investment banker Diamond was ousted following a scandal over the rigging of benchmark interest rates.
But Jenkins' plan to drive the bank's returns above its cost of capital - estimated at 11 percent - has been tripped up by a grim trading environment and uncertainty among staff about his vision for the investment bank, which has prompted the departure of some senior employees.
Jenkins, who had vowed to overhaul Barclays' high-risk, high-reward culture, then got into hot water with investors earlier this year when he raised bonuses for investment bankers despite a fall in profits.
A 41 percent slide in trading in debt, currencies and commodities in the first quarter, unveiled on Tuesday, put Barclays at the bottom of its peer group and laid bare the challenge he faces.
Since the start of the year, the Federal Reserve has passed tougher rules for foreign banks such as Barclays operating in the United States. The Bank of England has also said it wants British banks to go beyond an international rule on leverage, requiring them to set aside more money to cover future potential loses than foreign rivals.
Bad banks or non-core units have been deployed by a variety of banks in the wake of the financial crisis as a way of drawing a clear line between past business and future direction. They have also been used as a way of hiving off problematic loans, in countries such as Ireland, Spain and, more recently, Italy.
Eric Bommensath, currently co-head of Barclays' investment bank, will run the bad bank. Tom King, Bommensath's co-head, will take over sole responsibility for the investment bank.
As a result of the latest strategic review, Barclays will incur a further 800 million pounds of costs on top of 2.7 billion pounds already announced.
Additional reporting by Simon Jessop and Clare Hutchison; Writing by Carmel Crimmins; Editing by Tom Pfeiffer and Pravin Char


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Keeping your locks under control in the humid weather has never been easier. Ponytails are one of the biggest hair trends for spring and summer—and these sure aren't your typical schoolgirl styles.
Best Ponytails for Spring
Drew Barrymore
It's best to keep your hair pulled back when wearing a top with a high neck. Drew Barrymore perfected the look with a wavy textured ponytail and layered necklaces.
Ali Larter
A ponytail can be an effortless way to make a formal dress look fresh and modern. Actress Ali Larter showed off her effortless elegance (and those gorgeous earrings!) with a sweet pony at a red carpet event in L.A.
Thandie Newton
We're of course partial to Thandie's curly ponytail, it's really the statement making piece to her Cannes Film Festival look.
Hayden Panettiere
A ponytail is a fantastic style to sport when you're trying a bold makeup look, like this spring's popular hot pink lip!
Jayma Mays
This textured ponytail is all about imperfection. After you've tied your hair back, pull a few pieces out and tug to loosen the roots for a more tousled look. You can always pin back any pieces that aren't sitting right for a 'do that's perfectly imperfect.
Gwyneth Paltrow
Gwyneth's barely there makeup perfectly compliments her sporty hairstyle. The subtle center part is a simple way to add interest to the look.
Kim Kardashian
KK never looks anything but glam, and the same goes for her ponytail. This subtle pompadour style style looks extra chic with bold red lips and dramatic lashes.
Kristin Chenoweth
Kristin Chenoweth brought her ponytail around to the side to keep a glitzy dress looking of-the-moment. We think this style would look even more fabulous with natural curls or waves.
Jessica Chastain
Sexy, tousled bedhead is a perennial favorite, and easier to accomplish with naturally thick or voluminous hair. If you have thin or fine hair, this look might take a bit of teasing at the crown.
Kate Beckinsale
The messy, high ponytail is a Red Carpet go-to for many of Hollywood's starlets. At 39 years old, Kate is defying the laws of aging - and we think the high ponytail certainly helps!
Beyonce's black and white paintsuit moment at the 2013 Grammys is one we still can't forget, and that long sleek ponytail certainly contributed. Take a cue from the Queen and wrap an extra piece of hair around your elastic band for a fashion-forward style.
Denise Vasi
If you're looking for a dramatic change, a blown-out pony and even some extensions can have the high impact statement you're looking for.
Jessica Pare
Low ponytails can tend towards the stiff and stuffy, but in this case the bold dress, earrings and smoky eye needed an understated 'do to keep the look modern.
Olga Kuryleno
If you're looking for a fun way to update any hairstyle this spring and summer, add a braid or twist! This works with any style, but we love the way a braid spiced up this ponytail.
Selena Gomez
This voluminous ponytail is nearing Bump It heights (remember those?). The volume and pink lip keep Selena's black blazer looking young and fresh.


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Bogota Farm Strike Protest Turns Violent
Protests in support of a two-week old farmers strike in Colombia turned violent after riot police attempted to disperse demonstrators from Bogota's main square. WSJ's Dan Molinski reports via #WorldStream.
This transcript has been automatically generated and may not be 100% accurate.
... I ... I ... the the the ... use your Wall Street Journal ... it was today tens of thousands of protesters ... converged on the city's main square across the believer ... to support to retool ... farmers ... I ... the protest turned violent when riot police tried to force protesters to leave the city square ... this resulted in the protesters ... hurling rocks and bricks morning from nearby streets after police they smashed windows in many cases the buildings and stores ... police responded by firing water cannons there were many arrests for The Wall Street Journal this is a moment ...


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