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Identification of EcoHIV-Infected Cells in Microglia-Manipulated Transgenic Mice
Published on: December 20, 2024
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.
Abstract:
HIV-1 infection activates microglia and triggers neuroinflammation, which is the primary cause of HIV-associated neurological complications. Our previous study demonstrated that HIV-1 infection upregulates m6A modification in microglia, and in this study, we investigated the underlying regulatory mechanisms. Through viral protein screening, we identified Vpr as the protein responsible for increasing m6A modification. Further analysis revealed that HIV-1 infection reduces the level of the m6A demethylase ALKBH5. Vpr deleted HIV-1 infection and Q65R mutant Vpr expression experiments demonstrated that Vpr is capable of degrading ALKBH5 protein via the ubiquitin-proteasome pathway by interacting with ALKBH5. Addition of m6A inhibitors or overexpression of ALKBH5 inhibited Vpr-induced microglial activation and the production of inflammatory cytokines, suggesting that the upregulation of m6A modification might play a crucial role in microglial activation induced by Vpr. As microglial activation is a major cause of neuroinflammation leading to neuronal damage, this study provides new insights for understanding the interactions between HIV-1 and microglia, and might provide new ideas for the prevention strategies study on the neuroinflammation caused by HIV-1 infection.
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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