甲硫氨酸腺苷转移酶2A通过调控宿主一碳代谢促进HIV-1潜伏的机制

抗逆转录病毒药物无法根治HIV-1感染，病毒潜伏储存库的长期稳定存在是其主要原因，而HIV-1潜伏机制仍未解决。细胞代谢显著影响HIV-1在CD4+ T细胞的复制，但其是否参与调控HIV-1潜伏有待阐明。我们的预实验通过靶向1700余个代谢相关基因的CRISPR筛选，发现甲硫氨酸腺苷转移酶2A（MAT2A）可在细胞模型中促进HIV-1的潜伏感染。敲除MAT2A造成胞内S腺苷甲硫氨酸（SAM）水平下降，同时引起潜伏HIV-1的激活。对MAT2A敲除细胞添加外源的SAM可逆转潜伏病毒激活的表型。因此提出假说，MAT2A通过调控SAM介导的宿主一碳代谢促进HIV-1潜伏感染。本项目拟阐明MAT2A促进HIV-1潜伏的分子机制，并探索调控MAT2A及下游效应分子来干预HIV-1潜伏的可能性。本项目的实施将为激活（或压制）潜伏HIV-1提供新靶点，对发展艾滋病功能性治愈的新策略具有重要理论参考价值。

Antiretroviral drugs fail to eradicate HIV-1 infection, mainly due to the presence of a stable viral latent reservoir. Cellular metabolic activity has been shown to significantly affect HIV-1 replication in CD4+ T cells, but whether it regulates HIV-1 latency remains to be solved. Our preliminary experiment used CRISPR technology to screen for over 1700 metabolic genes and identified methionine adenosyltransferase 2A (MAT2A) as a facilitator of HIV-1 latent infection in a cellular model. MAT2A knockout decreases the intracellular level of S-adenosyl methionine (SAM), and promotes reactivation of latent HIV-1. Adding exogenous SAM to MAT2A knockout cells reverts the phenotype of latent HIV-1 reactivation. Therefore, we hypothesize that MAT2A promotes HIV-1 latent infection by regulating host one-carbon metabolism mediated by SAM. We propose to elucidate the molecular mechanism why MAT2A can promote HIV-1 latent infection, and explore the possibility of interfering viral latency by modulating MAT2A or its downstream effectors. This project will reveal novel targets for reactivating (or repressing) latent HIV-1, which will be of great theoretical importance to the development of new strategies for AIDS functional cure.