TAG HIV Basic Science, Vaccines, and Cure Project Blog

FDA Committe Votes to Approve Merck's HPV Vaccine, GARDASIL

Today (May 18), the FDA's Vaccines And Related Biological Products Advisory Committee met to discuss the approval of Merck's HPV vaccine candidate, GARDASIL. The panel voted unanimously for approval (13-0). Background briefing documents, including the FDA's analyses of the data from Merck's two large efficacy trials in women (Future I & II), are now available on the FDA dockets website. Transcripts from the hearing will also be posted there when they're available. The vaccine is expected to receive full FDA approval for marketing by June 8th. A number of media outlets have already picked up the story, including CNN Money, Associated Press, and Reuters.

Elite Control: CD8 T cells put pressure on HIV

Some rare HIV-infected individuals (perhaps 1 in 200) are able to suppress viral load to undetectable levels (less than 50 copies/mL) and maintain normal CD4 T cell counts in the absence of any therapy. Researchers have recently dubbed such individuals "elite suppressors" and intensive work is being undertaken to try and unravel the immunological, virological and host factors that underlie the phenomenon. One gene that is strongly associated with elite suppressor status is HLA B57. HLA genes manufacture (or, in genetic parlance, "encode") the receptors on T cells that allow them to lock onto and recognize viruses and other pathogens. HLA B57 encodes a CD8 T cell receptor that seems to render the cells particularly adept at responding to HIV.

In a paper just published in the May 15 issue of the Journal of Experimental Medicine, Joel Blankson and colleagues evaluate whether HIV mutates in an attempt to escape these CD8 T cell responses in elite suppressors (in a manner analogous to the way the virus can mutate and resist the effects of antiretroviral drugs). Perhaps surprisingly, they report that there is evidence of escape mutations occurring in viruses from elite suppressors, even though the viral load remains below 50 copies/mL. The escape mutations were found in all replicating viruses, but only rarely in inactive proviral HIV in resting memory CD4 T cells, suggesting that mutant viruses were not persisting long enough to establish a latent reservoir. The study authors put it thusly: "Despite the low frequency of mutations in proviral cellular gag, mutations in HLA-B*57–restricted epitopes were seen in every plasma virus amplified, suggesting powerful ongoing selective pressure targeting these epitopes. This study demonstrates that CTL escape mutations arise even in HIV-1–infected patients who have the best possible suppression of viremia."

The researchers also report that some individuals developed new CD8 T cell responses targeting the mutated HIV, which may contribute to their ability to maintain immunological control of viral replication. One function of CD8 T cells that was associated with the development of escape mutations was the production of the cytokine IL-2, suggesting that this may be a marker for a particularly functional CD8 T cell response. The production of interferon gamma, which is more commonly used when measuring CD8 T cell responses, did not seem to correlate. To put this another way, the parts of HIV being targeted by CD8 T cells capable of making IL-2 were likely to mutate in an attempt to escape CD8 T cell recognition, whereas the parts of HIV being targeted by CD8 T cells capable of making interferon gamma did not appear to be under so much pressure to mutate. The researchers conclude by stressing that "the relationship between CD8 T cell response and selection of escape mutations in elite suppressors may provide key insights into the mechanisms of effective suppression of HIV-1."

Recently, a new research effort was launched that aims to identify people with HIV that are elite suppressors and invite them to submit a blood sample for ongoing studies. The lead investigators are Drs. Eric Lander of Scripps Research, Dennis Burton of the Broad Institute and Bruce Walker of the Partners AIDS Research Center at the Mass General Hospital. Information about the study and contact information for the research coordinators is available on the Partners AIDS Research Center website.

http://www.jem.org/cgi/content/abstract/203/5/1357

JEM, Volume 203, Number 5, 1357-1369

Maintenance of viral suppression in HIV-1–infected HLA-B*57+ elite suppressors despite CTL escape mutations

Justin R. Bailey, Thomas M. Williams, Robert F. Siliciano, and Joel N. Blankson

Rare human immunodeficiency virus 1–infected individuals, termed elite suppressors (ES), maintain plasma virus levels of <50 copies/ml and normal CD4 counts without therapy. The major histocompatibility complex class I allele group human histocompatibility leukocyte antigen (HLA)-B*57 is overrepresented in this population. Mutations in HLA-B*57–restricted epitopes have been observed in ES, but their significance has remained unclear. Here we investigate the extent and impact of cytotoxic T lymphocyte (CTL) escape mutations in HLA-B*57+ ES. We provide the first direct evidence that most ES experience chronic low level viremia. Sequencing revealed a striking discordance between the genotypes of plasma virus and archived provirus in resting CD4+ T cells. Mutations in HLA-B*57–restricted Gag epitopes were present in all viruses from plasma but were rare in proviruses, suggesting powerful selective pressure acting at these epitopes. Surprisingly, strong CD8+ T cell interferon- responses were detected against some mutant epitopes found in plasma virus, suggesting the development of de novo responses to viral variants. In some individuals, relative CD8+ T cell interleukin-2 responses showed better correlation with the selection observed in vivo. Thus, analysis of low level viremia reveals an unexpectedly high level of CTL escape mutations reflecting selective pressure acting at HLA-B*57–restricted epitopes in ES. Continued viral suppression probably reflects CTL responses against unmutated epitopes and residual or de novo responses against epitopes with escape

Microbicides 2006

The 2006 Microbicides Conference just wrapped up in Cape Town, South Africa. AIDSMap has provided excellent coverage from its correspondent Theo Smart, including this excellent summary of the current pipeline: Microbicides 2006: what products are in the pipeline?

Webcasts from the conference are also available on the Kaiser Family Foundation website.