Researchers may finally be on track to get at the HIV that hides inside cells and keeps the infection going; if so, they could perhaps eradicate the virus from the body entirely, according to an article published in the July issue of Retrovirology. The latest research expands on the mixed results of earlier studies of valproic acid (Depakote), an epilepsy treatment that demonstrated potential as a method of purging HIV from its cellular hiding places.
After protease inhibitors were approved, researchers hoped that the new combination antiretroviral (ARV) therapy would be potent enough to burn out HIV infection over time. It soon became apparent, however, that no matter how strong the drugs are and how long a person’s virus levels remain undetectable, HIV can still hide out inside dormant cells and bring the infection flaring back to life once ARV meds are stopped. Therapies initially studied to reawaken these cells succeeded in forcing them to purge their HIV payload, but the therapies caused too much immune system inflammation. In other words, while they “turned on” the dormant cells, they also created so many susceptible uninfected CD4 cells that the ARV drugs couldn’t protect them.
What was needed, researchers argued, was a drug that could force out the HIV hiding within these cells without activating immune system cells at the same time. One such approach that has gained a lot of attention in recent years is the inhibition of histone deacetylase (HDAC), an enzyme believed to play a key role in maintaining HIV inside long-lived resting cells.
An early experiment with the HDAC inhibitor valproic acid proved promising. But another round of studies, reported a few years later in 2005, failed to show that valproic acid significantly affected the recalcitrant reservoirs of HIV-infected cells.
Four years later, Andrea Savarino, MD, PhD, from the Istituto Superiore di Sanità in Rome, and his colleagues have published the results of a study looking at a different HDAC inhibitor—entinostat (MS-275), currently being explored as an anti-cancer drug. Savarino’s group was able to awaken dormant cells, gain access to the hidden virus and kill it; however, they had to use doses of MS-275 that may be toxic to humans.
The researchers then tried using lower doses of entinostat in combination with buthionine sulfoximine, an experimental cancer drug that strips unhealthy cells of glutathione, a protective antioxidant. This approach was much more successful, allowing researchers to get at all of the hidden HIV without producing toxic effects. The authors plan to take their research next into animal models, and they remain hopeful about the potential for HIV eradication.