Learning to Silence HIV

by jeffrey Laurence, M.D.

January 12, 2009—Individuals successfully treated with antiretroviral drugs have little to no detectable HIV in their blood. What they do have is a very small number of cells, a million or so, infected with latent virus. In these cells, HIV has entered a state of dormancy, existing below the radar of a person’s immune system and beyond the ability of standard anti-HIV drugs to attack it. This latent HIV infection persists for the lifetime of the patient.

Two amfAR-funded research fellows, Drs. Young Kyeung Kim and Kara Lassen, have opened a window into just how this viral silencing occurs and what might be done to alter it. Writing in the December 2008 issue of the Journal of Virology, Drs. Kim, Lassen, and colleagues, working at Case Western Reserve University, noted that HIV typically enters a latent state when the function of one of its key regulating genes, known as Tat, is disrupted.

The researchers introduced just such a disruption in Tat by using an experimental method that produced mutations in the Tat protein. Given the high rate of HIV growth and the huge frequency with which HIV suffers genetic errors during its growth, this mutation didn’t take long to expand; at least in the test tube, half of all viruses were "silenced" by the mutation within about two months. This left the Case Western group with an intriguing puzzle: How did errors in Tat’s regulation relate to this process, how are Tat levels normally controlled in the absence of such functional disruptions, and how could researchers take advantage of these mechanisms to design new anti-HIV therapies?

HIV typically enters a latent state when the function of one of its key regulating genes, known as Tat, is disrupted.

Prior to this work, most investigators believed that HIV latency arose as a passive process, a consequence of HIV being carried along inside a cell as it progressed along a normal pathway of growth and differentiation. But Drs. Kim and Lassen show that this process is much more active than previously believed: Chemical modifications of histones, normal cell proteins that bind to the DNA of genes and help regulate their function, are critical. These modifications—acetylation and methylation—change gene structures, and one consequence of these changes is that any HIV integrated into those genes can be activated or silenced.

Silent HIV carries high levels of histone proteins lacking in acetylation but abundantly methylated. Certain immune hormones known as cytokines can turn on HIV growth by reversing these chemical modifications. But how might researchers take advantage of these insights to develop new therapies?

One approach was pioneered by Dr. David Margolis. Working with amfAR funding, he showed that drugs known as histone deacetylase (HDAC) inhibitors could activate latent HIV in the test tube, rendering the virus susceptible to attack by standard anti-HIV drugs. Although pilot trials of one such drug in patients did not show clear results, development of better HDAC inhibitors or related drugs may hold promise in the future.

Dr. Laurence is amfAR’s senior scientific consultant.