Dr. Galit Alter, Assistant Professor at the Ragon Institute, was awarded an NIH grant to identify new strategies to eliminate reservoir cells by a “shock and kill” approach.

In her grant application for which she was awarded $2 million in research funds, Dr. Alter proposes to test whether a class of monoclonal antibodies specific to HIV envelope may be designed that can kill infected cells after viral reactivation with small molecules such as histone deacetylase (HDC) inhibitors.

Over the past decade, HIV care has experienced a dramatic revolution due to new evidence that a cure for HIV may be possible. In the last few years, at least two instances of functional eradication of the virus have been published, one in an adult HIV patient in Berlin and one with an infant in Mississippi. Additionally, several suggestive cases have been reported in Paris and in a cohort of macaques in Portland. Together, these studies point to the possibility that new therapeutic approaches may make a cure a reality for those persons afflicted with HIV worldwide. With this renewed focus on HIV eradication, President Obama announced on World AIDS Day, December 1, 2013, that his administration is shifting $100 million into research efforts aimed at curing HIV.

Following acute infection, HIV establishes a latent reservoir in CD4+ T cells and other immune cells. However, recent studies strongly suggest that latency may be reversible through reactivation of the dormant virus. This reactivation alone would however not lead to eradication of the reservoir in itself, but would require active killing of those cells once the virus re-emerged. Therefore, additional directed destructive mechanisms are critically needed to rapidly eliminate cells that are reactivated. Currently, eradication efforts are centered around a “shock and kill” strategy aimed at driving the virus out of latency, followed by rapid removal of the infected cells through killer T cells.

Dr. Alter and her post-doctoral fellow, Dr. Zelda Euler, now propose a variation of this “shock and kill” strategy, where reactivated cells would instead be eliminated by killer antibodies, able to harness the killing activity of the innate immune system. This approach has been extensively exploited in the setting of cancer therapeutics that direct the cytolytic activity of Natural Killer (NK) cells to destroy tumor cells labeled with monoclonal antibody therapeutics. Likewise, Drs. Alter and Euler’s strategy involves the reversal of latency with small molecules such as HDAC inhibitors, which would allow HIV specific proteins to be presented on the cell surface. These HIV proteins would then be recognized by HIV-specific monoclonal antibodies with customized alterations to induce more and faster killing of labeled cells. While the virus may have historically escaped antibody immune pressure, a reservoir-targeting antibody therapeutic approach may benefit from the selection of a cocktail of previously cloned monoclonal antibodies that target highly conserved, broadly cross-reactive (not necessarily neutralizing), epitopes.

With this new grant and renewed confidence, Drs. Alter and Euler and her laboratory are forging ahead in the effort to find a functional cure for the plague of HIV infection.