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Emerg Microbes Infect. 2018 Aug 8;7(1):138. doi: 10.1038/s41426-018-0139-5.

TSC1 and DEPDC5 regulate HIV-1 latency through the mTOR signaling pathway.

Author information

1
Shanghai Public Health Clinical Center and Institutes of Biomedical Sciences, Key Laboratory of Medical Molecular Virology, Shanghai Medical College, Fudan University, Shanghai, China.
2
State Key Laboratory of Genetic Engineering and Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, School of Life Sciences, Fudan University, Shanghai, China.
3
Shanghai Public Health Clinical Center and Institutes of Biomedical Sciences, Key Laboratory of Medical Molecular Virology, Shanghai Medical College, Fudan University, Shanghai, China. zhangxiaoyan@shphc.org.cn.
4
Shanghai Public Health Clinical Center and Institutes of Biomedical Sciences, Key Laboratory of Medical Molecular Virology, Shanghai Medical College, Fudan University, Shanghai, China. xujianqing@shphc.org.cn.
5
State Key Laboratory for Infectious Disease Prevention and Control, China Centers for Disease Control and Prevention, Beijing, China. xujianqing@shphc.org.cn.

Abstract

The latent reservoir of HIV-1 presents a major barrier to viral eradication. The mechanism of the establishment and maintenance of the latent viral reservoir is not yet fully understood, which hinders the development of effective curative strategies. In this study, we identified two inhibitory genes, TSC1 and DEPDC5, that maintained HIV-1 latency by suppressing the mTORC1 pathway. We first adapted a genome-wide CRISPR screening approach to identify host factors required for HIV latency in a T-cell-based latency model and discovered two inhibitory genes, TSC1 and DEPDC5, which are potentially involved in HIV-1 latency. Knockout of either TSC1 or DEPDC5 led to enhanced HIV-1 reactivation in both a T-cell line (C11) and a monocyte cell line (U1), and this enhancement could be antagonized by the mTORC1 inhibitor rapamycin. Further evaluation of the mechanism revealed that TSC1 suppresses AKT-mTORC1-S6 via downregulation of Rheb, whereas DEPDC5 inhibits AKT-mTORC1-S6 through RagA. Overall, both TSC1 and DEPDC5 negatively regulate the AKT-mTORC1 pathway, and thus their agonists could be used in the development of new therapeutic approaches for activating HIV-1 latency.

PMID:
30087333
PMCID:
PMC6081400
DOI:
10.1038/s41426-018-0139-5
[Indexed for MEDLINE]
Free PMC Article

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