CPSF6 defines a conserved capsid interface that modulates HIV-1 replication

Krausslich, H.-G., Price, A. J., Fletcher, A. J., Schaller, T., Elliott, T., Lee, K., KewalRamani, V. N., Chin, J. W., Towers, G. J. and James, L. C. (2012) CPSF6 defines a conserved capsid interface that modulates HIV-1 replication. PLoS Pathogens, 8(8), e1002896. (doi: 10.1371/journal.ppat.1002896) (PMID:22956906) (PMCID:PMC3431306)

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Abstract

The HIV-1 genome enters cells inside a shell comprised of capsid (CA) protein. Variation in CA sequence alters HIV-1 infectivity and escape from host restriction factors. However, apart from the Cyclophilin A-binding loop, CA has no known interfaces with which to interact with cellular cofactors. Here we describe a novel protein-protein interface in the N-terminal domain of HIV-1 CA, determined by X-ray crystallography, which mediates both viral restriction and host cofactor dependence. The interface is highly conserved across lentiviruses and is accessible in the context of a hexameric lattice. Mutation of the interface prevents binding to and restriction by CPSF6-358, a truncated cytosolic form of the RNA processing factor, cleavage and polyadenylation specific factor 6 (CPSF6). Furthermore, mutations that prevent CPSF6 binding also relieve dependence on nuclear entry cofactors TNPO3 and RanBP2. These results suggest that the HIV-1 capsid mediates direct host cofactor interactions to facilitate viral infection.

Item Type:Articles
Additional Information:Funding was provided by: Medical Research Council (U105181010: AJP, AJF, TS, TE, JWC, GJT, LCJ); European Research Council (ERC 281627 - IAI); Wellcome Trust; National Institute for Health Research UCL/UCLH Comprehensive Biomedical Research Centre; Emmanuel College, Cambridge; National Cancer Institute’s intramural Center for Cancer Research.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Fletcher, Dr Adam
Authors: Krausslich, H.-G., Price, A. J., Fletcher, A. J., Schaller, T., Elliott, T., Lee, K., KewalRamani, V. N., Chin, J. W., Towers, G. J., and James, L. C.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:PLoS Pathogens
Publisher:Public Library of Science
ISSN:1553-7366
ISSN (Online):1553-7374
Copyright Holders:Copyright © 2012 The Authors
First Published:First published in PLoS Pathogens 8(8):e1002896
Publisher Policy:Reproduced under a Creative Commons licence

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