Nicolas Sluis-Cremer, PhD, has been awarded funding of $414,693 for a two-year R21 grant by the National Institutes of Health/National Institute of Allergy and Infectious Diseases (NIH/NIAID) entitled “Potent inhibition of HIV-1 latency reversal by PF-03758309”. This proposal was submitted in response to the competitive funding opportunity entitled “NIH Exploratory/Developmental Research Grant Program (Parent R21)” under funding opportunity number PA-20-195.
The persistence of latent, replication-competent HIV-1 proviruses in resting CD4+ T cells represents a major barrier to curing HIV-1 infection. To date, efforts to eradicate this viral reservoir have not led to complete, long-term viral suppression in either cell and/or animal models. Thus, we need to consider alternate approaches that could lead to a sterilizing or functional cure for HIV-1 infection. Our laboratory recently discovered that the p21-activated kinase (PAK) inhibitor PF-03758309 is an exceptionally potent inhibitor of HIV-1 latency reactivation (IC50 in the pM to low nM range) with a huge selectivity index (> 3,000). In the long term, we anticipate that PF-03758309 alone, or in combination with other drugs, could be used to facilitate a “block and lock” sterilizing cure in HIV-infected individuals. However, we do not know the mechanism(s) by which this inhibitor blocks reactivation of latent HIV-1 infection in CD4+ T cells. Indeed, preliminary studies in our laboratory revealed that its inhibition of HIV-1 latency reversal is not due to inhibition of the PAKs. The primary goal of this R21 proposal is to elucidate the mechanism(s) by which PF-03758309 silences HIV-1 proviruses. Collectively, the data derived from these studies will yield novel insights into the mechanisms associated with the maintenance of HIV-1 latency, and could identify new targets for drug development.