Foundation series

Improving HIV Latency Reversal Strategies – amfAR, The Foundation for AIDS Research

Research question
Eliminating reservoir cells persistently infected with HIV while leaving uninfected cells intact is the ultimate goal of HIV cure efforts and has eluded years of research. The development of new strategies is necessary. A recent study aimed to design a drug that would only be toxic in cells carrying the HIV protease, ie infected cells. The job of the HIV protease is to cut some of the other HIV proteins at a site called Phe-Pro.

The researchers speculated that they might take advantage of this feature by making a toxin that is only activated when the HIV protease cuts it. Such a drug would be a valuable partner with a latency reversing agent (LRA) in removing the HIV reservoir. Currently, “shock and kill” strategies, whereby an LRA is used to activate latently infected cells, rely on the immune system to kill these infected cells. A “medicinal killer agent” activated by the virus itself should prove to be of great help.

Results
The researchers, led by amfAR grantee Dr. Alexander Zelikin, started with MMAF, which is FDA-approved for a treatment of multiple myeloma, a cancer of the blood and bone marrow. It is highly toxic to cells because it interferes with tubulin, a protein essential for many normal cell functions. The research team designed a series of derivatives containing the Phe-Pro target site and added them to T cells latently infected with HIV in the test tube. Two of the derivatives, MF-6 and MF-7, increased the destruction of infected cells by more than tenfold when combined with LRA SAHA or TNF-α. Interestingly – and contrary to their hypothesis – an active HIV protease was not required for these drugs to work, and the HIV protease inhibitor saquinavir had no impact on their effectiveness. Instead, their cell-killing function seemed linked to their ability to simultaneously bind HIV protease and tubulin.

Impact
The authors conclude that their design of MMAF-derived drugs with LRAs could prove to be a powerful “pathogen-activated ART” strategy for the elimination of HIV reservoirs.

amfAR’s role
amfAR was a funder of this research.

original article
doi:10.1002/adtp.202200113

Dr. Laurence is amfAR’s Senior Scientific Consultant.