Thiostrepton Reactivates Latent HIV-1 through the p-TEFb and NF-κB Pathways Mediated by Heat Shock Response

Antimicrob Agents Chemother. 2020 Apr 21;64(5):e02328-19. doi: 10.1128/AAC.02328-19. Print 2020 Apr 21.

Abstract

Antiretroviral therapy (ART) suppresses HIV-1 replication but fails to cure the infection. The presence of an extremely stable viral latent reservoir, primarily in resting memory CD4+ T cells, remains a major obstacle to viral eradication. The "shock and kill" strategy targets these latently infected cells and boosts immune recognition and clearance, and thus, it is a promising approach for an HIV-1 functional cure. Although some latency-reversing agents (LRAs) have been reported, no apparent clinical progress has been made, so it is still vital to seek novel and effective LRAs. Here, we report that thiostrepton (TSR), a proteasome inhibitor, reactivates latent HIV-1 effectively in cellular models and in primary CD4+ T cells from ART-suppressed individuals ex vivo TSR does not induce global T cell activation, severe cytotoxicity, or CD8+ T cell dysfunction, making it a prospective LRA candidate. We also observed a significant synergistic effect of reactivation when TSR was combined with JQ1, prostratin, or bryostatin-1. Interestingly, six TSR analogues also show reactivation abilities that are similar to or more effective than that of TSR. We further verified that TSR upregulated expression of heat shock proteins (HSPs) in CD4+ T cells, which subsequently activated positive transcriptional elongation factor b (p-TEFb) and NF-κB signals, leading to viral reactivation. In summary, we identify TSR as a novel LRA which could have important significance for applications to an HIV-1 functional cure in the future.

Keywords: HIV-1; heat shock protein; latency reversal agent; latent reservoir; thiostrepton.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-HIV Agents / pharmacology*
  • Antiviral Agents / pharmacology*
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / virology
  • Cell Line
  • Drug Synergism
  • HIV Infections / drug therapy*
  • HIV Infections / virology
  • HIV-1 / drug effects*
  • Heat-Shock Proteins / drug effects*
  • High-Throughput Screening Assays
  • Humans
  • NF-kappa B / drug effects*
  • Positive Transcriptional Elongation Factor B / drug effects*
  • Prospective Studies
  • Signal Transduction / drug effects*
  • Thiostrepton / pharmacology*
  • Virus Activation / drug effects*
  • Virus Latency / drug effects*

Substances

  • Anti-HIV Agents
  • Antiviral Agents
  • Heat-Shock Proteins
  • NF-kappa B
  • Positive Transcriptional Elongation Factor B
  • Thiostrepton