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

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.

Acknowledgements

This work was supported by the Natural Science Foundation of China (NSFC#81561128008), the National Basic Research Program of China (973 Program#2014CB542502), and the National 13th Five-Year Grand Program on Key Infectious Disease Control (#2017ZX10202102).

Authors’ contributions

X.Z. and J.X. conceived the study. S.J. performed experiments. Q.L. performed the large-scale data analyses and functional analysis. J.C. assisted in CRISPR screens. L.Z. and Q.H. assisted with the WB analysis. S.J. wrote the manuscript. H.Z., X.Z., and J.X. supervised data analysis and revised the manuscript.

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Supplementary Information accompanies this paper at (10.1038/s41426-018-0139-5).

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