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AIDS 2012: HDAC Vorinostat Disrupts HIV Latency in Patients' CD4 Cells

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The histone deacetylase inhibitor vorinostat can interfere with a mechanisms that allows HIV to remain latent in resting CD4 T-cells, offering the potential to flush out the virus -- one approach being explored as a potential cure for HIV, researchers reported in the July 25, 2012, issue of Nature and at the XIX International AIDS Conference (AIDS 2012) last week in Washington, DC.

One of the factors that makes HIV so difficult to cure is that it integrates its genetic material into the chromosomes of host cells. In that state, the virus can maintain long-term latency, but HIV DNA can resume viral production if the cells become activated. Currently people with HIV must remain on antiretroviral therapy (ART) indefinitely to control resurgent virus emerging from activated T-cells.

One cure approach under study involves triggering latent HIV DNA in resting cells to begin producing new virus -- essentially flushing HIV out of hiding and making it vulnerable to antiretroviral drugs and natural immune responses. Prior laboratory and animal studies have shown that the cancer drug vorinostat (Zolinza, also known as suberoylanilide hydroxamic acid or SAHA) might accomplish this goal.

In a cell's nucleus DNA is coiled around structures called histones, allowing long chains of genetic material to fit into a small space. Acetylation and methylation are chemical changes that determine whether the DNA is condensed and unusable or expanded so it can be used to build new proteins. Histone deacetylases (HDACs) are enzymes that keep DNA tightly bound and inaccessible. HDAC inhibitors reverse this process, enabling expression of viral DNA and production of new virus particles.

Nancie Archin and David Margolis from the University of North Carolina at Chapel Hill and colleagues evaluated whether the HDAC inhibitor vorinostatcan disrupt HIV latency in people on ART.

The researchers collected resting CD4 cells from 8 men with fully suppressed viral load while on antiretroviral treatment. After a single dose of vorinostat, participants showed a significant increase in HIV gene expression -- rising by nearly 5-fold in these cells -- as well as higher levels of associated biomarkers.

"This demonstrates that a molecular mechanism known to enforce HIV latency can be therapeutically targeted in humans, provides proof-of-concept for histone deacetylase inhibitors as a therapeutic class, and defines a precise approach to test novel strategies to attack and eradicate latent HIV infection directly," the study authors wrote.

This study is the first to show that vorinostat can reactivate latent HIV in patients. Sharon Lewin at Monash University in Melbourne and her group are conducting similar studies of this approach.

These findings show that "we can disrupt latency and force the virus out into the open," Margolis said at a July 26 press conference on HIV cure research. The next step, he added, is to figure out how to apply this to all latent CD4 cells in the body, while protecting new cells from infection. Margolis was careful, however, not to prematurely characterize this work as a cure.

In a Nature editorial Steven Deeks from the University of California at San Francisco and incoming International AIDS Societypresident Francoise Barré-Sinoussi -- co-chairs of the IASTowards an HIV Cure initiative -- cautioned that studies such as this raise ethical concerns about giving toxic drugs to people with HIV who are otherwise healthy on ART. At the AIDS 2012 cure press conference Barré-Sinoussi announced that an ethics working group has been established to address this and other issues related to cure research.

8/3/12

Reference

NM Archin, AL Liberty, AD Kashuba, DM Margolis, et al. Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy, Nature 487(7408):482-485. July 25, 2012.

S Deeks and F Barré-Sinoussi. Public health: Towards a cure for HIV. Nature487(7407):293-294. July 19, 2012.

Other Sources

University of North Carolina. Pioneering study shows drug can purge dormant HIV. Press release, July 25, 2012.

International AIDS Society. New HIV Cure Research Released Today at the XIX International AIDS Conference (AIDS 2012). Press release. July 26, 2012.