amfAR, The Foundation for AIDS Research

“Shock and Kill” Strategy Holds Promise in the Search for a Cure

By Jeffrey Laurence, M.D., and Rowena Johnston, Ph.D.

HIV cannot be cured by antiretroviral therapy (ART). Why not? Because ART only works when the virus is actively replicating, and in all infected people, a tiny fraction─around one in a million─of infected cells carries a latent form of the virus that is not actively replicating. In order to overcome this obstacle, scientists have come up with a strategy colloquially known as “shock and kill,” which would use drugs to “shock” the latent virus into replicating. This active virus, and the cells producing the virus, would then be “killed” by ART and by normal immune system processes (or other interventions specifically designed to kill infected cells), thereby ridding the body of virus and curing the HIV infection. The trick would be to find a drug that can “shock” the virus while doing no undue harm to the patient.

Several years ago, one group of researchers thought they had done just that using valproic acid or VPA, a medication approved for epilepsy. VPA, one of a family of drugs known as HDAC inhibitors, alters the genetic environment, permitting the latent virus to become active. In 2005, they reported that in a small number of patients VPA, in combination with an intensified ART regimen, appeared to decrease the amount of T cells harboring active virus within one month of treatment. However, writing in the January issue of HIV Medicine, amfAR grantee Jean-Pierre Routy of McGill University and colleagues present evidence that, while the “shock and kill” strategy remains plausible, VPA does not seem to be the way to go.

In this new study, Routy enrolled 56 subjects whose virus was suppressed by ART, meaning that most remaining virus was latent, and added VPA to the regimen of some of them, selected randomly. Contrary to the desired outcome of a “shock and kill” strategy, no significant reduction in the amount of T cells with replicating virus was seen after up to eight months of such treatment. CD4+ T cell counts also did not improve. These negative data parallel other smaller studies with VPA.

Routy and colleagues concluded, “Additional combined strategies using more potent HDAC inhibitors might be required to sufficiently induce HIV-1 gene expression in infected cells which could potentially lead to HIV eradication.” In fact, we reported to you a few months ago that amfAR grantees Jonathan Karn and Mudit Tyagi had discovered, through test-tube experiments, that there are at least two distinct processes capable of activating, or “shocking” HIV, suggesting that more than one type of stimulus may be capable of or required for the shock. This concept is currently being tested in a pilot study in patients utilizing the FDA approved drug disulfiram, commonly used in alcohol abuse prevention programs. It is spearheaded by a collaboration between Dr. Steven Deeks of University of California-San Francisco and Dr. Robert Siliciano of Johns Hopkins University, utilizing an amfAR-funded program known as ARCHE (amfAR Research Consortium on HIV Eradication).

We’ll keep you posted on the results.

Dr. Laurence is amfAR’s senior scientific consultant.