HIV-1 Vpr activates microglia by upregulating m6A modification through ubiquitin-proteasome pathway-mediated

Qian Peng1, Weiling Li2, Feng Qian3

  • 1Hubei Key Laboratory of Cognitive and Affective Disorders, Institute of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan, China.

Virulence
|March 13, 2026
PubMed

Insights

HIV-1 infection increases m6A modification in microglia via the Vpr protein, leading to neuroinflammation. Inhibiting this process may offer new strategies for preventing HIV-associated neurological damage.

Area of Science:

  • Neuroscience
  • Virology
  • Immunology

Background:

  • HIV-1 infection activates microglia, causing neuroinflammation and neurological complications.
  • Microglial activation is linked to the N6-methyladenosine (m6A) modification pathway.

Purpose of the Study:

  • To investigate the mechanisms by which HIV-1 infection upregulates m6A modification in microglia.
  • To identify the specific viral protein responsible for this upregulation and its downstream effects.

Main Methods:

  • Viral protein screening to identify key players in m6A modification.
  • Experiments using Vpr-deleted HIV-1 and mutant Vpr to assess ALKBH5 degradation.
  • Utilizing m6A inhibitors and ALKBH5 overexpression to evaluate effects on microglial activation.

Main Results:

  • HIV-1 infection upregulates m6A modification in microglia, mediated by the viral protein Vpr.
  • Vpr interacts with and promotes the degradation of the m6A demethylase ALKBH5 via the ubiquitin-proteasome pathway.
  • Inhibition of m6A modification or ALKBH5 overexpression suppressed Vpr-induced microglial activation and inflammatory cytokine production.

Conclusions:

  • Upregulation of m6A modification by HIV-1 Vpr plays a critical role in microglial activation and neuroinflammation.
  • Targeting the Vpr-ALKBH5 interaction and m6A modification presents a potential therapeutic strategy for HIV-associated neurological disorders.

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