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CPSF6 Defines a Conserved Capsid Interface that Modulates HIV-1 Replication

Price, AJ; Fletcher, AJ; Schaller, T; Elliott, T; Lee, K; KewalRamani, VN; Chin, JW; ... James, LC; + view all (2012) CPSF6 Defines a Conserved Capsid Interface that Modulates HIV-1 Replication. PLOS PATHOGENS , 8 (8) , Article e1002896. 10.1371/journal.ppat.1002896. Green open access

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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.

Type: Article
Title: CPSF6 Defines a Conserved Capsid Interface that Modulates HIV-1 Replication
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.ppat.1002896
Publisher version: http://dx.doi.org/10.1371/journal.ppat.1002896
Language: English
Additional information: This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Funding: 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. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity
URI: https://discovery.ucl.ac.uk/id/eprint/1370448
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