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

Abstract

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.

HIV-1 replication and latency are balanced by mTOR-driven cell metabolism

“…Corroborating the importance of DNA methylation in HIV-1 latency, Yang et al. found that knocking out methionine adenosyltransferase 2A (MAT2A) in the J-Lat 9.2 cell line led to HIV-1 latency reversal ( Yang et al., 2021 ). MAT2A creates SAM (S-Adenosylmethionine), the methyl donor in histone and DNA methylation, indicating the importance of SAM for maintenance of latency.…”

“…Yang et al. further investigated the HIV-1 LTR in the MAT2A knockout and showed decreased CpG island methylation by approximately 50% as well as decreased methylation of histones around the HIV-1 LTR, such as H3K4me3, H3K9me3, and H3K27me3 ( Yang et al., 2021 ). To validate their findings, Yang et al.…”

“…used primary CD4 + T cells treated with SAM to increase methyl availability and silencing of the HIV-1 genome. After treatment with two latency reversing agents, PMA and ionomycin, latency persisted, indicating the strength of methylation in maintaining latency ( Yang et al., 2021 ). These findings show the role of one-carbon metabolism and methyl group availability in the epigenetic control of HIV-1.…”

Rapid metabolic regulation of a novel arginine methylation of KCa3.1 attenuates T cell exhaustion

“…1A). Among the amino acids important for T cells, Met is the sole amino acid responsible for cellular methylome maintenance via the S-adenosyl Met (SAM) pathway, and alterations in the SAM pathway adversely affect T cell function ( 10, 11 ). In complete media, no significant changes were observed in SAM or S-adenosyl homocysteine (SAH) (Fig.…”

High-throughput CRISPR technology: a novel horizon for solid organ transplantation

“…conducted a CRISPR knockout screen in an HIV-1 latently infected cell line (J-Lat 9.2) with a human CRISPR metabolic gene knockout library. They found that MAT2A-mediated one-carbon metabolism contributes to regulating HIV latency ( 102 ).…”