Michael Palm Basic Science, Vaccines and Prevention Weblog

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By Richard Jefferys, Project Coordinator

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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