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

Proc Natl Acad Sci U S A. 2020 Jul 7;117(27):15763-15771. doi: 10.1073/pnas.1916290117. Epub 2020 Jun 22.


HIV-1 latency is a major barrier to cure. Identification of small molecules that destabilize latency and allow immune clearance of infected cells could lead to treatment-free remission. In vitro models of HIV-1 latency involving cell lines or primary cells have been developed for characterization of HIV-1 latency and high-throughput screening for latency-reversing agents (LRAs). We have shown that the majority of LRAs identified to date are relatively ineffective in cells from infected individuals despite activity in model systems. We show here that, for diverse LRAs, latency reversal observed in model systems involves a heat shock factor 1 (HSF1)-mediated stress pathway. Small-molecule inhibition of HSF1 attenuated HIV-1 latency reversal by histone deactylase inhibitors, protein kinase C agonists, and proteasome inhibitors without interfering with the known mechanism of action of these LRAs. However, latency reversal by second mitochondria-derived activator of caspase (SMAC) mimetics was not affected by inhibition of HSF1. In cells from infected individuals, inhibition of HSF1 attenuated latency reversal by phorbol ester+ionomycin but not by anti-CD3+anti-CD28. HSF1 promotes elongation of HIV-1 RNA by recruiting P-TEFb to the HIV-1 long terminal repeat (LTR), and we show that inhibition of HSF1 attenuates the formation of elongated HIV-1 transcripts. We demonstrate that in vitro models of latency have higher levels of the P-TEFb subunit cyclin T1 than primary cells, which may explain why many LRAs are functional in model systems but relatively ineffective in primary cells. Together, these studies provide insights into why particular LRA combinations are effective in reversing latency in cells from infected individuals.

Keywords: HIV; HSF1; LRA; latency; reservoir.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-HIV Agents / pharmacology
  • Apoptosis Regulatory Proteins / genetics
  • Cyclin T / genetics
  • HIV Infections / genetics*
  • HIV Infections / virology
  • HIV-1 / genetics*
  • HIV-1 / pathogenicity
  • Heat Shock Transcription Factors / antagonists & inhibitors
  • Heat Shock Transcription Factors / genetics*
  • Histone Deacetylase Inhibitors / pharmacology
  • Humans
  • Mitochondrial Proteins / genetics
  • Positive Transcriptional Elongation Factor B / genetics
  • Protein Kinase C / genetics
  • RNA, Viral / drug effects
  • RNA, Viral / genetics
  • Small Molecule Libraries / pharmacology
  • Terminal Repeat Sequences / genetics
  • Virus Activation / genetics
  • Virus Latency / genetics*


  • Anti-HIV Agents
  • Apoptosis Regulatory Proteins
  • CCNT1 protein, human
  • Cyclin T
  • DIABLO protein, human
  • HSF1 protein, human
  • Heat Shock Transcription Factors
  • Histone Deacetylase Inhibitors
  • Mitochondrial Proteins
  • RNA, Viral
  • Small Molecule Libraries
  • Positive Transcriptional Elongation Factor B
  • Protein Kinase C