Interfering residues narrow the spectrum of MLV restriction by human TRIM5alpha.
TRIM5alpha is a restriction factor that limits infection of human cells by so-called N- but not B- or NB-tropic strains of murine leukemia virus (MLV). Here, we performed a mutation-based functional analysis of TRIM5alpha-mediated MLV restriction. Our results reveal that changes at tyrosine(336) of human TRIM5alpha, within the variable region 1 of its C-terminal PRYSPRY domain, can expand its activity to B-MLV and to the NB-tropic Moloney MLV. Conversely, we demonstrate that the escape of MLV from restriction by wild-type or mutant forms of huTRIM5alpha can be achieved through interdependent changes at positions 82, 109, 110, and 117 of the viral capsid. Together, our results support a model in which TRIM5alpha-mediated retroviral restriction results from the direct binding of the antiviral PRYSPRY domain to the viral capsid, and can be prevented by interferences exerted by critical residues on either one of these two partners.
Maillard
Pierre V
PV
Global Health Institute, School of Life Sciences, Frontiers in Genetics National Center for Competence in Research, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
Reynard
Séverine
S
Serhan
Fatima
F
Turelli
Priscilla
P
Trono
Didier
D
D019943:Amino Acid Substitution; D000818:Animals; D000090103:Antiviral Restriction Factors; D002213:Capsid / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002477:Cells; D005347:Fibroblasts / Q000166:cytology / Q000276:immunology / Q000821:virology*; D015658:HIV Infections / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000254:growth & development; D006801:Humans; D007668:Kidney / Q000166:cytology; D009052:Leukemia Virus, Murine / Q000235:genetics / Q000254:growth & development* / Q000276:immunology; D051379:Mice; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D012192:Retroviridae Infections / Q000276:immunology / Q000821:virology*; D000070584:Tripartite Motif Proteins; D014412:Tumor Virus Infections / Q000276:immunology / Q000821:virology*; D044767:Ubiquitin-Protein Ligases
D000090103:Antiviral Restriction Factors; D002352:Carrier Proteins; D000070584:Tripartite Motif Proteins; C477346:TRIM5 protein, human; D044767:Ubiquitin-Protein Ligases