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.
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.
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.