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)

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 > School of Infection & Immunity; College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
• 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