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CROI 2012: Vorinostat -- A First Step on the Road Towards a Cure for HIV

Researchers from the University of North Carolina at Chapel Hill have for the first time shown that HIV can be purged from resting latent T-cells, an important early step in moving research forward on one of the potential HIV cure strategies, according to a report at the 19th Conference on Retroviruses and Opportunistic Infections (CROI 2012) last week in Seattle.

The news was presented at a promising session on HIV latency and eradication. The Wednesday afternoon session was so popular that there were 2 overflow rooms for participants who could not fit into the presentation room.

For several years, David Margolis at UNC has been interested in finding ways to unlock sleeper or resting CD4 memory T-cells that hide latent HIV from the immune response and from effective antiretroviral therapy. Theoretically, if HIV can be released into the plasma from these cells, antiretroviral drugs can move in to mop up the remaining virus. In this small, elegant, and convincing first phase study, the biological plausibility of this theory has passed the first hurdle.

The proof-of-concept trial used a single dose of a histone deacetylase (HDAC) inhibitor known as vorinostat or SAHA (suberoylanilide hydroxamic acid), which is marketed as a treatment for cutaneous lymphoma under the brand name Zolinza. Histone deacetylase is an important enzyme that contributes to maintaining latency of HIV genetic material integrated into human cells.

The goal was to release or break HIV latency, "turning on" the integrated genes and making them start producing new virus. Margolis and others have studied various HDAC inhibitors, including valproic acid (used to treat epilepsy), but this is the first study in HIV positive participants that proved to work.

The study looked at 6 HIV positive men who had been on stable antiretroviral regimens with viral load less than 50 copies/mL and CD4 cell counts above 500 cells/mm³. Their average age was 45 years old.

First, CD4 cells were removed from participants by leukapheresis and tested to establish baseline virus levels inside the cell. Then the cells were exposed to vorinostat, and HIV RNA was measured to show whether HDAC was inhibited.

The second step was to make sure the selected dose of 400 mg had an effect on the HDAC enzyme. Finally, the cells were compared before and after the single dose of vorinostat.

Results

• There was a 2-fold increase in histone acetylation within 8 hours of receiving a single dose of vorinostat.
• A single dose of vorinostat induced expression of HIV RNA within latently infected resting CD4 T-cells in all 6 patients.
• There was an average 4.8-fold increase in HIV RNA in resting cells; there was a wide variance among participants, with HIV RNA increases ranging from 1.5-fold to 10-fold.
• HIV RNA was not detected in blood plasma; no change in plasma viral RNA levels could be seen using a single copy assay.
• The single 400 mg dose of vorinostat was safe and well tolerated.

"This proves for the first time that there are ways to specifically treat viral latency, the first step towards curing HIV infection," Margolis stated. "It shows that this class of drugs, HDAC inhibitors, can attack persistent virus. Vorinostat may not be the magic bullet, but this success shows us a new way to test drugs to target latency, and suggests that we can build a path that may lead to a cure."

Vorinostat is AMES positive, a test that shows mutagenesis (ability to cause mutations), which could potentially lead to cancer. However, since this study only used a single dose, there were no adverse events related to the study drug. It is hoped that the use of vorinostat in this trial is the first indication that the HDAC drug class can be effective, and other drugs that are less toxic and not AMES positive will be examined as research towards a cure moves forward.

Margolis' eradication team at University of North Carolina is also leading one of the research collaborations in the NIH-funded Martin Delaney Collaboratory: Towards and HIV-1 Cure; grants were also awarded to researchers at the University of California at San Francisco and the Fred Hutchinson Cancer Research Center. Margolis’ group received the largest amount -- $6.3 million each year for 5 years -- with the goal of further elucidating HIV reservoirs and latency with vorinostat and newly discovered HDAC inhibitors from Merck. 

Vorinostat in Australia

[Sharon Lewin talks to Matt Sharp about a related vorinostat study ongoing in Australia. CROI 2012 interview, Seattle, March 8, 2012. Production facility courtesy of IFARA]

3/15/12

N Archin, A Liberty, A Kashuba, D Margolis, et al. Administration of Vorinostat Disrupts HIV-1 Latency in Patients on ART. 19th Conference on Retroviruses and Opportunistic Infections. Seattle, March 5-8, 2012. Abstract 157LB.

University of North Carolina at Chapel Hill. Drug Helps Purge Hidden HIV Virus, Study Shows. Press release. March 8, 2012.

J Cohen. Big Bolus for HIV/AIDS Cure Research. Science. July 11, 2011