MAT2A-Mediated S-Adenosylmethionine Level in CD4⁺ T Cells Regulates HIV-1 Latent Infection

Area of Science:

• Virology
• Molecular Biology
• Immunology

Background:

• Antiretroviral drugs control HIV-1 replication but cannot eliminate the latent viral reservoir, hindering a cure.
• Understanding HIV-1 latency mechanisms is crucial for developing novel therapeutic strategies.
• The role of cellular metabolism in HIV-1 latency remains largely unexplored.

Purpose of the Study:

• To investigate the role of metabolic genes in regulating HIV-1 latency.
• To identify molecular targets for a functional HIV-1 cure.

Main Methods:

• A CRISPR library knockout screen of 1773 metabolic genes in an HIV-1 latent infection model.
• Assessed HIV-1 reactivation and viral DNA/histone methylation.
• Correlated plasma S-Adenosylmethionine (SAM) levels with HIV-1 DNA in patients.

Main Results:

• Methionine Adenosyltransferase 2A (MAT2A) was identified as a key regulator of HIV-1 latency.
• MAT2A knockout enhanced latent HIV-1 reactivation; MAT2A overexpression suppressed it.
• MAT2A modulates latency via SAM-mediated one-carbon flux, affecting DNA and 5'-LTR methylation.
• Plasma SAM levels positively correlated with HIV-1 DNA in treated individuals.

Conclusions:

• MAT2A-mediated one-carbon metabolism is critical for regulating HIV-1 latency.
• MAT2A and SAM are potential therapeutic targets and biomarkers for HIV-1 latency.
• This research offers new avenues for developing strategies toward a functional HIV-1 cure.