HIV Transcription Inhibition by Newly Identified p300 Inhibitors
Abstract
Understanding the mechanism of HIV-1 transcription is key for developing a new class of antiviral drugs. HIV-1 Tat is an essential protein that transactivates HIV transcription by binding to the TAR region of HIV mRNA. p300-mediated acetylation of Tat is required for transactivation of the HIV long terminal repeat. Full activation of the HIV promoter also requires nuclear factor kappa-B (NF!B), which activates HIV transcription. Full activation of NF_B also requires p300-mediated acetylation. Since salicylic acid inhibits NF_B and HIV-1 transcription (1), we tested whether it also inhibits p300 acetyltransferase activity. Indeed, we find that p300 activity is inhibited both in vitro and in vivo by salicylic acid. A secondary screen of FDA-approved chemical compounds that contain structures similar to salicylic acid identified p300 inhibitors that are more potent than salicylic acid. We focused on the effects of sodium salicylate and diflunisal on HIV transcription. We found that sodium salicylate and diflunisal inhibit HIV transcription at concentrations within the range measured in patients receiving these drugs. We propose to further test these drugs on HIV replication and reactivation from latent infection. We will test the hypothesis that these drugs inhibit HIV transcription via suppression of Tat and NF_;B acetylation.