Summary of HIV Cure Research Presented at CROI 2012

The 19^th 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.

Research into curing HIV infection featured prominently at the meeting, building on the case of Timothy Brown that was reported for the first time on a poster at CROI four years ago. A symposium on the subject was held from 4-6pm on Wednesday March 7^th and featured several excellent overview presentations on the state of the science. The major message that emerged from data presentations on cure-related research was that a one-two punch may be needed to address HIV reservoirs: firstly, dormant HIV in latently infected cells must be awakened and, secondly, effective T cell responses are likely to be required to deliver the coup de grace and kill the HIV-infected cells that are induced to produce virus.

The rationale for this two-pronged approach was encapsulated in presentations by David Margolis from the University of North Carolina and Liang Shan from Johns Hopkins University. Margolis showed that administration the HDAC inhibitor vorinostat (also known as SAHA) successfully induced latently infected cells to express HIV RNA in six trial participants on ART (up from the four participants Margolis was able to discuss last December at the HIV persistence workshop). Liang Shan described laboratory experiments demonstrating that HIV-specific CD8 T cells from individuals with chronic HIV infection are generally unable to kill CD4 T cells that are induced to produce virus by exposure to vorinostat. In many cases, this failure could be overcome by stimulating the HIV-specific CD8 T cells with HIV antigens immediately prior to mixing them with the HIV-infected CD4 T cells, suggesting to Shan and colleagues that therapeutic immunization should be combined with anti-latency drugs (the paper containing these results was published by the journal Immunity on the same day as Shan's CROI talk, click here and scroll down to see the abstract).

Although the goal of finding and killing latently infected cells is central to cure research efforts, it is not applicable to all strategies under study. Gene modification approaches that aim to make susceptible cells resistant to HIV -- and thereby potentially give the immune system the upper hand against the virus -- continue to be studied, with Sangamo BioSciences in the lead with their approach that abrogates expression of the HIV co-receptor CCR5 on CD4 T cells. Currently, the delivery of Sangamo's treatment requires removal of CD4 T cells by apheresis, followed by modification and expansion of the cells in the laboratory and reinfusion into the individual. Another technique that is being explored in non-human primates involves gene modification of stem cells, which give rise to CD4 T cells and other cell types and therefore might be a better target. The research group of Hans-Peter Kiem at Fred Hutchinson Cancer Research Center in Seattle presented a "proof of concept" study showing that a gene encoding an HIV entry inhibitor (C46) could be introduced into stem cells in macaques, ultimately leading to substantial levels of circulating gene-modified CD4 T cells (~20%). When these animals were challenged with an SIV/HIV hybrid SHIV virus, CD4 T cell levels dipped but recovered and the proportion of gene gene-modified CD4 T cells increased. Interestingly, unmodified CD4 T cells also appeared to be protected from infection, leading the researchers to speculate that gene-modified CD4 T cells were contributing to more effective virus-specific immune responses in the treated macaques. Kiem's group plans to conduct similar studies using Sangamo's technology to disrupt the CCR5 gene in stem cells.

Richard Jefferys is the coordinator of the Michael Palm HIV Basic Science, Vaccines & Prevention Project Weblog at the Treatment Action Group (TAG). The original blog post may be viewed here.