Reinvigorating the Search for a Cure
By Richard Jefferys
In Vienna, Austria, on July 16 and 17, 2010, immediately prior to the XVIII International AIDS Conference, the International AIDS Society (IAS) held a workshop titled “Towards a Cure: HIV Reservoirs and Strategies to Control Them.” Cosponsors included the French National Agency for Research on AIDS and Viral Hepatitis, the German Bundesministerium für Wissenschaft und Forschung, the U.S. National Institutes of Health, Sidaction and Treatment Action Group (TAG). Chaired by IAS president elect and Nobel laureate Françoise Barré-Sinoussi, the workshop was a high-profile illustration of the reinvigoration of the research effort toward curing HIV infection.
Over the two days, attendees—including basic and clinical researchers, policy makers, community advocates, and journalists—heard presentations covering a range of relevant topics including viral sanctuary sites and cellular reservoirs, mechanisms of HIV latency, novel therapeutic approaches, and drug development issues. There is a fairly broad consensus among scientists that antiretroviral therapy (ART) is capable of completely suppressing HIV replication in most individuals; as mentioned by both Steve Deeks and Frank Maldarelli at the workshop, the evidence supporting this conclusion includes the lack of HIV evolution in people on long-term suppressive ART; the homogenous nature of the very low levels of virus that are detectable despite ART (suggesting this virus emerges from cells that were infected prior to ART initiation as opposed to reflecting ongoing replication); and the absence of a reduction in residual viral load levels in most studies that have attempted to “intensify” ART by adding additional drugs.
There is, however, some evidence that HIV replication may occur and contribute to viral persistence. At the workshop Joe Wong presented data suggestive of low-level replication in the terminal ileum of the gut, and Una O’Doherty debuted results indicating that the virus replicates sporadically in some individuals. O’Doherty’s results were obtained with a new assay that measures the amount of HIV DNA integrated into cellular DNA compared to the amount of unintegrated HIV DNA; an “excess” of the latter is suggestive of active replication.
Researchers presented a variety of potential therapeutic approaches. Sandrina Da Fonseca showed that a cellular marker named PD-1 is preferentially expressed on memory CD4 T cells harboring HIV, and inhibiting PD-1 may awaken the silent viral genomes in these cells. PD-1 inhibitors are currently in human trials for the treatment of cancer, and Da Fonseca suggested they deserve evaluation as a potential reservoir depleting strategy in HIV. Much discussion centered around drugs called HDAC inhibitors, which have been shown to activate latent HIV in vitro. Daria Hazuda from Merck described a study in monkeys in which an HDAC inhibitor and another drug called a protein kinase C activator were added to ART; the approach reduced virus levels in tissues but did not prevent a rebound in viral replication when ART was interrupted.
The researcher David Margolis is currently planning a human trial of an HDAC inhibitor named SAHA. Brigitte Autran outlined the design of two trials (named Eramune 01 and 02) that will evaluate the effect of adding immune-based therapies to ART. Eramune 01 will explore ART intensification plus modulation of the immune system with IL-7, a cytokine that may be able to deplete latent HIV from memory CD4 T cells. Eramune 02 involves the addition of a therapeutic vaccine to intensified ART, with the goal of bolstering the ability of the immune system to specifically recognize and eliminate HIV-infected cells. Details of both trials are available in the clinical trials database at http://www.clinicaltrials.gov.
At the close of the workshop, Françoise Barré-Sinoussi stressed that IAS is committed to making cure-related research an ongoing priority. Full presentations and rapporteur summaries of each session are available on the IAS website at http://www.iasociety.org/Default.aspx?pageId=349. A meeting report will be published in the Journal of the International AIDS Society before the end of 2010. In addition to the IAS workshop, a number of other recent developments have helped push the search for a cure back to the top of the research agenda:
- The non-profit organization amfAR has instituted a targeted program supporting collaborative cure-related research, named the amfAR Research Consortium for HIV Eradication (ARCHE). Rowena Johnston from amfAR provides the background to this program in an open-access article published in the journal AIDS Research and Human Retroviruses at http://www.liebertonline.com/doi/full/10.1089/ aid.2010.0087.
- The NIH has issued a request for funding applications for a “collaboratory” project to accelerate and streamline cure research: http://grants.nih.gov/grants/guide/rfa-files/RFA-AI-10-009.html. The idea derives from an opinion piece published by Doug Richman and colleagues in the journal Science. The project has been named in honor of one of the authors of the opinion piece, the AIDS activist and founder of Project Inform, Martin Delaney, who died last year.
- In the July 9, 2010, issue of Science, an article reviewing issues that need to be addressed in cure research was published by Didier Trono, Carine Van Lint, Christine Rouzioux, Eric Verdin, Françoise Barré-Sinoussi, Tae-Wook Chun, and Nicolas Chomont: http://www.sciencemag.org/cgi/content/short/329/5988/174.
- Ahead of the 2010 International AIDS Conference, a community-based organization called the AIDS Policy Project issued a report on cure research calling for more funding and summarizing current approaches; the report is available online at http://www.aidspolicyproject.org.
- TAG held a workshop in November 2008 along with amfAR and Project Inform at which many of the issues leading to this year’s progress were discussed: http://www.treatmentactiongroup.org/tagline/2008/fall/tag-sponsors-cure-.... Plans are being developed for another such workshop focusing on clinical and regulatory issues related to studies of potential HIV curative approaches to take place early next year.