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

PLoS Pathog. 2012;8(8):e1002896. doi: 10.1371/journal.ppat.1002896. Epub 2012 Aug 30.

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.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Antiviral Agents / metabolism
  • Capsid Proteins / chemistry
  • Capsid Proteins / genetics
  • Capsid Proteins / metabolism*
  • Cell Line, Tumor
  • Conserved Sequence
  • Crystallography, X-Ray
  • HIV Infections / virology*
  • HIV-1 / genetics
  • HIV-1 / physiology*
  • Humans
  • Indoles / metabolism
  • Models, Molecular
  • Molecular Chaperones / metabolism
  • Molecular Sequence Data
  • Mutation
  • Nuclear Pore Complex Proteins / metabolism
  • Phenylalanine / analogs & derivatives
  • Phenylalanine / metabolism
  • Protein Binding
  • Sequence Alignment
  • Virus Internalization
  • Virus Replication*
  • beta Karyopherins / metabolism
  • mRNA Cleavage and Polyadenylation Factors / genetics
  • mRNA Cleavage and Polyadenylation Factors / metabolism*

Substances

  • Antiviral Agents
  • Capsid Proteins
  • Indoles
  • Molecular Chaperones
  • Nuclear Pore Complex Proteins
  • PF-3450074
  • TNPO3 protein, human
  • beta Karyopherins
  • cleavage factor Im, human
  • mRNA Cleavage and Polyadenylation Factors
  • ran-binding protein 2
  • Phenylalanine

Associated data

  • PDB/4B4N