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

PLoS Pathogens

Vineet N. KewalRamani¹  KyeongEun Lee¹  Adam J. Fletcher²  Torsten Schaller²  Greg J. Towers²  Amanda J. Price³  Tom Elliott³  Jason W. Chin³  Leo C. James³ 

[1] HIV Drug Resistance Program, National Cancer Institute, Frederick, Maryland, United States of America;Medical Research Council Centre for Medical Molecular Virology, Division of Infection and Immunity, University College London, London, United Kingdom;Medical Research Council Laboratory of Molecular Biology, Division of Protein and Nucleic Acid Chemistry, Cambridge, United Kingdom

关键词: HIV-1;    Viral packaging;    Cofactors (biochemistry);    Crystal structure;    HIV-2;    HeLa cells;    Nuclear import;    Microbial mutation;   

DOI  :  10.1371/journal.ppat.1002896

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY