BET inhibitors RVX-208 and PFI-1 reactivate HIV-1 from latency

Sci Rep. 2017 Nov 30;7(1):16646. doi: 10.1038/s41598-017-16816-1.

Abstract

Persistent latent reservoir in resting CD4+ T cells is a major obstacle in curing HIV-1 infection. Effective strategies for eradication of the HIV-1 reservoir are urgently needed. We report here for the first time that two BET inhibitors, RVX-208, which has entered phase II clinical trials for diverse cardiovascular disorders, and PFI-1, which has been widely studied in oncology, can reactivate HIV-1 from latency. RVX-208 and PFI-1 treatment alone or in combination with other latency reversing agents efficiently reactivated HIV-1 transcription through an up-regulation of P-TEFb by increasing CDK9 Thr-186 phosphorylation in latently infected Jurkat T cells in vitro. The two BET inhibitors also reactivated HIV-1 transcription in cART treated patient-derived resting CD4+ T cells ex vivo, without influence on global immune cell activation. Our findings, in combination with previous reports, further confirm that BET inhibitors are a group of leading compounds for combating HIV-1 latency for viral eradication.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD4 Antigens / metabolism
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • CD4-Positive T-Lymphocytes / virology
  • Cyclin-Dependent Kinase 9 / metabolism
  • HIV Infections / drug therapy
  • HIV Infections / virology*
  • HIV-1 / drug effects*
  • HIV-1 / physiology*
  • Humans
  • Jurkat Cells
  • Phosphorylation
  • Quinazolinones / chemistry
  • Quinazolinones / pharmacology*
  • Receptors, CCR5 / metabolism
  • Tumor Necrosis Factor-alpha / metabolism
  • Virus Activation / drug effects*
  • Virus Latency / drug effects*
  • tat Gene Products, Human Immunodeficiency Virus / metabolism

Substances

  • CCR5 protein, human
  • CD4 Antigens
  • Quinazolinones
  • Receptors, CCR5
  • Tumor Necrosis Factor-alpha
  • tat Gene Products, Human Immunodeficiency Virus
  • apabetalone
  • CDK9 protein, human
  • Cyclin-Dependent Kinase 9