Testing “Shock and Kill”
By Jeffrey Laurence, M.D.
A recurring theme in HIV cure research is the barrier presented by persistent HIV infection. Current antiretroviral therapies (ART) can reduce active virus growth to undetectable levels but there remains an extremely stable reservoir of dormant virus invulnerable to attack by these drugs. One strategy to overcome this obstacle is to reactivate, or ‘shock,’ these infected cells—inducing the production of HIV susceptible to being killed by ART.
Two years ago, as part of a research project led by Dr. Robert Siliciano under the auspices of the amfAR Research Consortium on HIV Eradication (ARCHE), it was discovered that disulfiram, an FDA-approved drug for the treatment of alcoholism, could activate latent HIV in the test tube. Writing in the March issue of Clinical Infectious Diseases, ARCHE members Drs. Adriana Andrade, Adam Spivak, Robert and Janet Siliciano, and Steven Deeks, along with their colleagues, describe a pilot study testing disulfiram (also known as Antabuse) in a small group of HIV-positive individuals.
Three institutions were involved in this project: the University of Utah, Salt Lake City; Johns Hopkins University School of Medicine, Baltimore, Maryland; and the University of California, San Francisco. Researchers recruited 16 individuals, all responding well to ART as evidenced by high CD4 T cell counts while on treatment and very low viral loads (less than 50 copies of HIV per milliter of blood) for a median of six and a half years. The size of their latent reservoir was measured two weeks before and 10 weeks after administration of 500mg of disulfiram, given daily for 14 days.
The team found that, overall, disulfiram had no significant effect on the size of the latent reservoir. However, in a small subset of the volunteers, low levels of virus increased almost fourfold after the first dose of drug. This increase in detectable viremia suggests that disulfiram might have been having the intended effect—shocking previously latent virus out of infected cells. The researchers concluded that too small a dose of drug may have been used to fully reverse latency in more of the study participants; fewer than half had measurable disulfiram levels.
The authors also suggested that simply activating virus may be insufficient to destroy the infected T cells from which that virus is shocked. If those cells remained, only to become dormant again, little would be accomplished. “The study presented here suggests that ‘shock and kill’ strategies with drugs such as disulfiram will likely require another step to prime the immune system to clear virus-producing T cells,” stated the research team in their report. And this is indeed another avenue of amfAR-funded research.
Dr. Laurence is amfAR’s senior scientific consultant.