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High Throughput In Vitro Assessment of Latency Reversing Agents on HIV Transcription and Splicing
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BET inhibitors RVX-208 and PFI-1 reactivate HIV-1 from latency

Panpan Lu1, Yinzhong Shen2, He Yang1

  • 1State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, 200438, China.

Scientific Reports
|December 2, 2017
PubMed

Insights

Two BET inhibitors, RVX-208 and PFI-1, effectively reactivate latent HIV-1 (Human Immunodeficiency Virus type 1) by up-regulating P-TEFb. This finding offers a promising strategy for HIV-1 reservoir eradication.

Area of Science:

  • Virology
  • Immunology
  • Pharmacology

Background:

  • The persistent latent reservoir in resting CD4+ T cells is a significant barrier to curing HIV-1 infection.
  • Developing effective strategies for HIV-1 reservoir eradication is a critical research priority.

Purpose of the Study:

  • To investigate the potential of BET inhibitors, RVX-208 and PFI-1, in reactivating latent HIV-1.
  • To explore the mechanism by which these BET inhibitors reverse HIV-1 latency.

Main Methods:

  • Treatment of latently infected Jurkat T cells and ex vivo patient-derived resting CD4+ T cells with BET inhibitors RVX-208 and PFI-1.
  • Assessment of HIV-1 transcription reactivation and P-TEFb pathway modulation, including CDK9 Thr-186 phosphorylation.
  • Evaluation of global immune cell activation.

Main Results:

  • RVX-208 and PFI-1 demonstrated the ability to reactivate HIV-1 transcription from latency, both individually and in combination with other latency-reversing agents.
  • The reactivation mechanism involves up-regulation of P-TEFb via increased CDK9 Thr-186 phosphorylation.
  • HIV-1 reactivation was observed in ex vivo settings using patient-derived cells without inducing global immune cell activation.

Conclusions:

  • BET inhibitors RVX-208 and PFI-1 are effective in reactivating latent HIV-1.
  • These compounds represent a promising therapeutic avenue for targeting the HIV-1 reservoir and achieving viral eradication.

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