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

• Published in: Frontiers in immunology 2021-09, Vol.12, p.745784-745784
• Main Authors: Yang, Xiaofan, Huang, Ting, Wang, Tiantian, Gao, Hongbo, Zhang, Haitao, Peng, Wen, Zhao, Jiacong, Hu, Shujing, Lu, Panpan, Hong, Zhongsi, Li, Bo, Deng, Kai
• Format: Article
• Language: English
• Subjects: Adult; Anti-HIV Agents - therapeutic use; Carbon - metabolism; CD4+ T cell; CD4-Positive T-Lymphocytes - enzymology; CD4-Positive T-Lymphocytes - immunology; CRISPR-Cas Systems; DNA, Viral - blood; Gene Knockout Techniques; Gene Library; HEK293 Cells; Histone Code; HIV Infections - blood; HIV Infections - drug therapy; HIV Infections - immunology; HIV Long Terminal Repeat; HIV-1; HIV-1 - physiology; Humans; Immunology; Jurkat Cells; latent infection; Latent Infection - blood; Latent Infection - immunology; MAT2A; Methionine Adenosyltransferase - physiology; one-carbon flux; RNA Interference; RNA, Small Interfering - genetics; S-Adenosylmethionine - blood; Virus Activation
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2021.745784

Antiretroviral drugs effectively halt HIV-1 replication and disease progression, however, due to the presence of a stable viral latent reservoir, the infection cannot be cured by antiretroviral drugs alone. Elucidating the molecular mechanisms underlying HIV-1 latent infection remains a critical hurdle that precludes the development of novel therapeutic strategies aiming for a potential functional cure. Cellular metabolism has been reported to affect HIV-1 replication in CD4 T cells, but it remains largely unclear whether it is involved in the regulation of HIV-1 latency. Here, we performed a sub-pooled CRISPR library knockout screen targeting 1773 metabolic-related genes in a cell model of HIV-1 latent infection and found that Methionine Adenosyltransferase 2A (MAT2A) contributes to HIV-1 latency. MAT2A knockout enhanced the reactivation of latent HIV-1 while MAT2A overexpression did the opposite. Mechanistically, MAT2A modulates HIV-1 latency through S-Adenosylmethionine (SAM)-mediated one-carbon flux. MAT2A knockout resulted in a significant downregulation of DNA and histone methylation at the HIV-1 5'-LTR. Importantly, we found that the plasma level of SAM is positively correlated with HIV-1 DNA in PBMCs from ART-treated infected individuals, suggesting SAM could serve as a potential biomarker for the latent viral reservoir. Overall, this study reveals an important role of MAT2A-mediated one-carbon metabolism in regulating HIV-1 latency and provides a promising target for the development of new strategies for a functional cure of HIV-1.