It remains clear that the primary obstacle to curing HIV is the latent reservoir of virus that is impervious to standard antiretroviral drugs and persists under the radar of an immune system attack. Dr. Eric Verdin and colleagues at the Gladstone Institute of Virology and Immunology, with scientists from the Howard Hughes Medical Institute, the University of California, San Francisco (UCSF), the Karolinska Institute in Sweden, and Johns Hopkins University, have uncovered a new pathway by which HIV maintains its dormant state.
The authors note that, thus far, no effective strategies have emerged that either efficiently activate latent HIV, an essential part of a “shock and kill” strategy of HIV eradication, or block its reactivation, a curative strategy known as “block and lock.”
Verdin and associates embarked on what is colloquially known as a fishing expedition. They used an “ultracomplex shRNA screen” and identified mTOR (mechanistic target of rapamycin) as centrally important in HIV latency. This normal cell protein kinase has long been known as a sensor for nutrients—amino acids, lipids, and other growth factors—required for a cell’s survival. Normally, if mTOR-controlled systems find these nutrients low, cell division is suppressed. When they are abundant, cell division is allowed to proceed. As such, this pathway is a key part of novel anti-cancer strategies, because the objective of cancer treatment is to limit rapid cell growth.
In experiments detailed in the December 2016 issue of Cell Host & Microbe, the authors found that mTOR inhibitors such as rapamycin, similar to those used in both cancer therapy and as an immune suppressant in organ and tissue transplants, can also block HIV latency reversal in test tube systems using patient cells. They modestly conclude that this work “may have therapeutic implications” in terms of an HIV cure.
Two amfAR grantees, Drs. Timothy Henrich and Peter Stock, both at UCSF, are conducting clinical studies of mTOR inhibitors in HIV-infected people to determine what effect these drugs may have on latent reservoirs of HIV.
Dr. Laurence is amfAR’s senior scientific consultant.