HSF1 inhibition attenuates HIV-1 latency reversal mediated by several candidate LRAs In Vitro and Ex Vivo

• DOI: 10.1073/pnas.1916290117
• Publication Date: 2020-06-23T00:35:42Z
• Authors: Andrew Timmons; Emily Fray; Mithra Kumar; Fengting Wu; Weiwei Dai; Cynthia Korin Bullen; Peggy Kim; Carrie Hetzel; Chao Yang; Subul Beg; Jun Lai; Joel L. Pomerantz; Steven A. Yukl; Janet D. Siliciano; Robert F. Siliciano
• Keywords: reservoir; Anti-HIV Agents; HIV Infections; HSF1; Mitochondrial Proteins; Small Molecule Libraries; Heat Shock Transcription Factors; 2.1 Biological and endogenous factors; Humans; Positive Transcriptional Elongation Factor B; Viral; Aetiology; latency; Protein Kinase C; Cyclin T; Terminal Repeat Sequences; HIV; Virus Latency; 3. Good health; Histone Deacetylase Inhibitors; LRA; HIV-1; HIV/AIDS; RNA; RNA, Viral; Virus Activation; Apoptosis Regulatory Proteins

Significance The latent reservoir for HIV-1 is a major barrier to curing the infection. Current cure strategies are focused on eliminating the reservoir through a two-step “shock and kill” approach involving the use of small-molecule latency-reversing agents (LRAs) followed by immune interventions to kill infected cells. Numerous candidate LRAs have been identified in studies using in vitro models of latency, but none have been shown to reduce the reservoir in vivo. We show here that many candidate LRAs work through an unexpected pathway involving the transcription factor HSF1, a result with implications for developing effective combinations of LRAs for use in HIV cure strategies.