amfAR, The Foundation for AIDS Research

Destroying HIV Reservoirs

By Jeffrey Laurence, M.D.

Robert Siciliano
Dr. Robert Siliciano
A recurring theme in HIV cure research is the formidable barrier presented by latent HIV infection. Current antiretroviral therapies (ART) are superb in reducing active virus growth to undetectable levels. But there remains an extremely stable reservoir of virus—predominantly in resting memory CD4+ T cells—invulnerable to attack by these drugs.

One strategy to overcome this latent reservoir is to activate the latent cells, inducing active virus, which would then be susceptible to ART. But as Dr. Robert Siliciano and colleagues, funded by an amfAR ARCHE grant, point out in the March issue of the journal Immunity, there is a major problem with this “shock and kill” approach. Contrary to initial expectations, those latently infected T cells do not die after viral activation and can continue to harbor HIV in a latent state.

Dr. Siliciano, working at Johns Hopkins University with colleagues from the National Taiwan University and the Howard Hughes Medical Institute, utilized a test-tube model for HIV reservoirs. In one of a series of experiments, they added a potent chemical inducer of HIV growth, SAHA, to cells from HIV-positive individuals on ART. SAHA is an FDA-approved drug used to treat a type of skin lymphoma, and it has been tested in HIV-positive individuals for its ability to activate latent HIV. As expected, SAHA induced HIV growth in all nine samples examined. But six days later, the frequency of latently infected cells was no different from parallel samples that hadn’t been activated by SAHA. Normally, an infected cell dies after virus is produced within it. But in this case, the damage caused by provoking HIV growth with SAHA was not sufficient to kill the cells and thereby remove their reservoir potential.

By and large, adding CD8+ “killer” T cells (CTLs) from patients on ART—which are generally very good at killing HIV-infected cells—didn’t help either. They were either defective in some way or there were too few to do any damage. What did work was a vaccination strategy. Pre-exposing those killer cells to proteins from the core of the virus—a kind of vaccination in a Petri dish, using a Gag antigen—enabled them to destroy SAHA-activated reservoir cells.

This is a major finding in the field of cure research. It suggests that a combined approach—coupling the boosting of HIV-specific immunity by vaccination with virus activation by drugs such as SAHA—will be needed to attack latent reservoirs. The authors appropriately concluded, “Our study strongly suggests that boosting CTL responses through vaccination prior to virus reactivation may be essential for eradication of HIV-1 infection.”

Dr. Laurence is amfAR’s senior scientific consultant.