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Sorafenib enforces HIV-1 latency by selectively inhibiting PKC-driven STAT1/3 serine 727 phosphorylation

Peipei Wang1, Zhuoyue Meng2,3, Jiasheng Zhou4

  • 1Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.

Antimicrobial Agents and Chemotherapy
|August 3, 2026
PubMed

Insights

Scientists found a new way to keep HIV-1 latent by targeting protein kinase C (PKC) and STAT1/3 phosphorylation. This discovery using sorafenib may help develop a functional cure for HIV-1.

Area of Science:

  • Virology
  • Immunology
  • Molecular Biology

Background:

  • The latent HIV-1 reservoir is a significant obstacle to a functional cure.
  • The "block-and-lock" strategy aims for sustained proviral silencing to prevent viral rebound.
  • Understanding the molecular basis of stable HIV-1 latency is crucial.

Purpose of the Study:

  • To identify novel regulatory mechanisms controlling HIV-1 transcriptional reactivation.
  • To investigate the role of protein kinase C (PKC)-dependent STAT1/3 phosphorylation in HIV-1 latency.
  • To evaluate sorafenib as a potential agent for promoting HIV-1 latency.

Main Methods:

  • Investigated PKC-dependent phosphorylation of STAT1 and STAT3 at serine 727.
  • Utilized sorafenib, a multi-kinase inhibitor, to target the identified regulatory axis.
  • Assessed HIV-1 reactivation in various latency models and primary CD4+ T cells.
  • Analyzed JAK-STAT and PI3K-Akt signaling pathway activation.
  • Evaluated sorafenib's cytotoxicity and effects on immune cell markers.

Main Results:

  • Identified STAT1/3 serine 727 phosphorylation as a key regulator of HIV-1 reactivation.
  • Sorafenib effectively suppressed HIV-1 reactivation and promoted latency establishment in vitro.
  • Sorafenib selectively inhibited PKC-mediated STAT1/3 phosphorylation without affecting tyrosine phosphorylation.
  • Disruption of STAT1/3 phosphorylation blocked transcriptional activation at the HIV-1 LTR.
  • Sorafenib demonstrated no significant cytotoxicity or adverse effects on CD4+ T cell activation/exhaustion markers.

Conclusions:

  • STAT1/3 serine 727 phosphorylation is a critical checkpoint in regulating HIV-1 latency.
  • Sorafenib is a promising agent for promoting HIV-1 latency and advancing functional cure strategies.
  • Targeting this pathway offers a novel approach to controlling the latent HIV-1 reservoir.
Keywords:
HIV-1STAT1/3 Ser727latency-promoting agentsorafenib

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