title: Retrovirus restriction by TRIM5 proteins requires recognition of only a small fraction of viral capsid subunits.
abstract: The host restriction factors TRIM5α and TRIMCyp potently inhibit retrovirus infection by binding to the incoming retrovirus capsid. TRIM5 proteins are dimeric, and their association with the viral capsid appears to be enhanced by avidity effects owing to formation of higher-order oligomeric complexes. We examined the stoichiometric requirement for TRIM5 functional recognition by quantifying the efficiencies of restriction of HIV-1 and murine leukemia virus (MLV) particles containing various proportions of restriction-sensitive and -insensitive CA subunits. Both TRIMCyp and TRIM5α inhibited infection of retrovirus particles containing as little as 25% of the restriction-sensitive CA protein. Accordingly, we also observed efficient binding of TRIMCyp in vitro to capsid assemblies containing as little as one-fourth wild-type CA protein. Paradoxically, the ability of HIV-1 particles to abrogate TRIMCyp restriction in trans was more strongly dependent on the fraction of wild-type CA than was restriction of infection. Collectively, our results indicate that TRIM5 restriction factors bind to retroviral capsids in a highly cooperative manner and suggest that TRIM5 can engage a capsid lattice containing a minimum of three or fewer recognizable subunits per hexamer. Our study supports a model in which localized binding of TRIM5 to the viral capsid nucleates rapid polymerization of a TRIM5 lattice on the capsid surface.
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Jiong
authors.initials: J
authors.lastname: Shi
authors.forename: David B
authors.initials: DB
authors.lastname: Friedman
authors.forename: Christopher
authors.initials: C
authors.lastname: Aiken
mesh_terms: D000818:Animals; D000090103:Antiviral Restriction Factors; D002213:Capsid / Q000276:immunology* / Q000378:metabolism; D002352:Carrier Proteins / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D009052:Leukemia Virus, Murine / Q000276:immunology*; D011485:Protein Binding; D055503:Protein Multimerization; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases
chemical_list: D000090103:Antiviral Restriction Factors; D002352:Carrier Proteins; D000070584:Tripartite Motif Proteins; C477346:TRIM5 protein, human; D044767:Ubiquitin-Protein Ligases