Journal
PLOS PATHOGENS
Volume 8, Issue 8, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.ppat.1002896
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Funding
- Medical Research Council [U105181010]
- 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
- Medical Research Council [MC_U105181010, G9721629, G0801172, MC_U105181009] Funding Source: researchfish
- MRC [G0801172, MC_U105181009, G9721629, MC_U105181010] Funding Source: UKRI
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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.
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