CD81 association with SAMHD1 enhances HIV-1 reverse transcription by increasing dNTP levels

Abstract

In this study, we report that the tetraspanin CD81 enhances human immunodeficiency virus (HIV)-1 reverse transcription in HIV-1-infected cells. This is enabled by the direct interaction of CD81 with the deoxynucleoside triphosphate phosphohydrolase SAMHD1. This interaction prevents endosomal accumulation and favours the proteasome-dependent degradation of SAMHD1. Consequently, CD81 depletion results in SAMHD1 increased expression, decreasing the availability of deoxynucleoside triphosphates (dNTP) and thus HIV-1 reverse transcription. Conversely, CD81 overexpression, but not the expression of a CD81 carboxy (C)-terminal deletion mutant, increases cellular dNTP content and HIV-1 reverse transcription. Our results demonstrate that the interaction of CD81 with SAMHD1 controls the metabolic rate of HIV-1 replication by tuning the availability of building blocks for reverse transcription, namely dNTPs. Together with its role in HIV-1 entry and budding into host cells, the data herein indicate that HIV-1 uses CD81 as a rheostat that controls different stages of the infection.

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Fig. 1: The C-terminal domain of CD81 mediates its association with SAMHD1.
Fig. 2: CD81 expression supports R5-tropic HIV-1 RT.
Fig. 3: CD81 regulates X4-tropic HIV-1 RT.
Fig. 4: CD81 negatively regulates cellular dNTP content through SAMHD1.
Fig. 5: CD81 regulates SAMHD1 expression.
Fig. 6: SAMHD1 is partially enriched at early endosomes.

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Acknowledgements

The authors thank M. Vicente-Manzanares (Hospital de la Princesa, UAM, Spain) for critical reading of the manuscript. Microscopy was performed at CNIC Microscopy & Dynamic Imaging Unit. This work was supported by grants to S.L. (Translational Cancer Award from Stanford Cancer Institute, SPARK at Stanford, and the Breast Cancer Research program from the Department of Defense grant W81XWH-14-1-0397); to B.K. (R01 GM104198; R01 AI049784); to M.A.M.-F. (RD16/0025/0019; PI16/01863; CYTED 214RT0482); to F.S.-M. (SAF2014-55579-R; INDISNET-S2011/BMD-2332; ERC-2011-AdG 294340-GENTRIS; PIE13/00041) and to MY-M (BFU2014-55478-R; Fundación Ramón Areces; RYC-2012-11025); and was co-funded by Fondo Europeo de Desarrollo Regional (FEDER). The CNIC is supported by the Spanish Ministry of Economy and Competitiveness (MINECO) and the Pro CNIC Foundation. FV-C was supported by The American Association of Immunologist through a Careers in Immunology Fellowship; and HS by a FPI-UAM Fellowship.

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V.R.P., F.S.M. and M.Y.M. conceived and designed research. V.R.P., H.S., S.A., S.L.M., G.L. and M.Y.M. performed experimental work. S.A., F.V.C., S.L., B.K., M.A.M.F., F.S.M. and M.Y.M. provided reagents. V.R.P. and M.Y.M. analysed the data. V.R.P. wrote the paper.

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Correspondence to Maria Yáñez-Mó.

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Rocha-Perugini, V., Suárez, H., Álvarez, S. et al. CD81 association with SAMHD1 enhances HIV-1 reverse transcription by increasing dNTP levels. Nat Microbiol 2, 1513–1522 (2017). https://doi.org/10.1038/s41564-017-0019-0

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