Shocking HIV Out of Hiding: How Are We Doing?

The key obstacle to an HIV cure remains the reservoir of persistent virus, which is impervious to standard anti-HIV drugs. It has been a target of numerous research teams, many of which are focused on a “shock and kill” approach: dormant HIV-infected cells are activated and thus rendered susceptible to drug- and immune-based attack.

Dr. Sharon Lewin

However, although a few trials of latency-reversing agents (LRAs) in HIV-positive patients on antiretroviral therapy (ART) have shown the expected increase in cell-associated HIV genetic material in T cells, the frequency of those patients’ latently infected cells hasn’t budged. Writing in the July issue of Current Opinion in HIV and AIDS, amfAR-funded scientist Dr. Sharon Lewin of the University of Melbourne, along with Dr. Thomas Rasmussen from Aarhus University Hospital in Denmark, suggests three reasons for this persistent failure in the clinic.

First, such a strategy demands a robust shock to the latent state. More effective LRAs, possibly used in cocktails similar to combination ART, are required. Second, immune responses that are potent enough to kill those induced virus-expressing cells are needed. Finally, Drs. Lewin and Rasmussen believe more attention should be paid to the role of immune escape mutations among newly awakened virus, i.e., viruses that may evade attempts to destroy them using vaccine strategies or antibodies.

Dr. Warner Greene

amfAR is funding several groups to examine those issues, in the test tube and in clinical trials. A recent proof of concept for this approach was provided by amfAR-funded scientist Dr. Warner Greene and colleagues at the University of California, San Francisco. Writing in the prestigious journal Nature Medicine, they recognized that certain types of retinoic acid—vitamin A-based derivatives—can activate genes that increase HIV growth as well as preferentially induce the death of HIV-infected cells.

One of these derivatives is acitretin, an FDA-approved pill for the treatment of psoriasis. Dr. Greene and associates discovered that acitretin was particularly effective in decreasing proviral DNA—a sensitive marker for latency—in CD4+ T cells of HIV-positive individuals on ART, particularly when used together with a common LRA known as SAHA.

At the moment these are promising test-tube experiments. But the authors conclude that their model might be the improved “shock and kill” strategy needed to eliminate all HIV-infected cells.

Dr. Laurence is amfAR’s senior scientific consultant.

Antibodies as an Important Part of an HIV Cure Strategy

Last month, we reviewed the work of amfAR-funded scientist Dr. Nancy Haigwood of Oregon Health and Science University, who is exploring how to block mother-to-child transmission of HIV. She used a monkey model and a “passive immunotherapy” strategy based on a cocktail of two potent antibodies capable of neutralizing a broad spectrum of AIDS viruses. In the April issue of Nature Medicine, she and her colleagues wrote, “early passive immunotherapy can eliminate early viral foci and thereby prevent the establishment of viral reservoirs.” And anything that can affect HIV reservoirs is of strong interest to cure researchers.

This point is now being aggressively pursued by amfAR Krim Fellow Dr. Stylianos Bournazos and associates working in the laboratory of Dr. Jeffrey Ravetch at The Rockefeller University in New York. Writing in a May issue of the prestigious journal Science, the researchers reported utilizing a single broadly neutralizing anti-HIV antibody to target infected CD4+ T cells in mice with a humanized immune system (i.e., mice that have been injected with human stem cells). They found that the survival of infected cells could be greatly decreased by this antibody through a process involving an immune receptor known as Fc gamma.

This work is important as antibodies differ from anti-HIV drugs in that they can alter the survival times of both cell-free virus and infected cells. They can also recruit host immune cells to defend against the virus. A variety of different strains of HIV obtained directly from patients were used in this mouse model, and the antibody was equally effective against all of them. In addition, another mouse model mimicking chronic HIV infection demonstrated that such antibodies can accelerate clearance of cells after a longer-term HIV infection.

The authors concluded with this promising statement: “The finding that antibodies can clear infected cells in vivo has important implications for therapies aimed at HIV prevention and viral reservoir reduction or elimination.”

Dr. Laurence is amfAR’s senior scientific consultant.