title: Homology-based identification of capsid determinants that protect HIV1 from human TRIM5α restriction.
abstract: The tropism of retroviruses relies on their ability to exploit cellular factors for their replication as well as to avoid host-encoded inhibitory activities such as TRIM5α. N-tropic murine leukemia virus is sensitive to human TRIM5α (huTRIM5α) restriction, whereas human immunodeficiency virus type 1 (HIV1) escapes this antiviral factor. We previously revealed that mutation of four critical amino acid residues within the capsid can render murine leukemia virus resistant to huTRIM5α. Here, we exploit the high degree of conservation in the tertiary structure of retroviral capsids to map the corresponding positions on the HIV1 capsid. We then demonstrated that, when changes were introduced at some of these positions, HIV1 becomes sensitive to huTRIM5α restriction, a phenomenon reinforced by additionally mutating the nearby cyclophilin A binding loop of the viral protein. These results indicate that retroviruses have evolved similar mechanisms to escape TRIM5α restriction via the interference of structurally homologous determinants in the viral capsid.
authors.affiliation: From the Global Health Institute, School of Life Sciences, and "Frontiers in Genetics" National Center for Competence in Research, Ecole Polytechnique Fédérale de Lausanne and.
authors.forename: Pierre V
authors.initials: PV
authors.lastname: Maillard
authors.affiliation: the Swiss Institute of Bioinformatics, Molecular Modeling Group, Genopode Building, 1015 Lausanne, Switzerland.
authors.forename: Vincent
authors.initials: V
authors.lastname: Zoete
authors.affiliation: the Swiss Institute of Bioinformatics, Molecular Modeling Group, Genopode Building, 1015 Lausanne, Switzerland,; the Ludwig Institute for Cancer Research, Ltd., 1066 Epalinges, Switzerland, and; the Pluridisciplinary Centre for Clinical Oncology (CePO), Lausanne University Hospital (CHUV), 1011 Lausanne, Switzerland.
authors.forename: Olivier
authors.initials: O
authors.lastname: Michielin
authors.affiliation: From the Global Health Institute, School of Life Sciences, and "Frontiers in Genetics" National Center for Competence in Research, Ecole Polytechnique Fédérale de Lausanne and. Electronic address: didier.trono@epfl.ch.
authors.forename: Didier
authors.initials: D
authors.lastname: Trono
mesh_terms: D000818:Animals; D000090103:Antiviral Restriction Factors; D036022:Capsid Proteins / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D019143:Evolution, Molecular; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D009052:Leukemia Virus, Murine / Q000502:physiology*; D051189:Murinae; D009154:Mutation; D017433:Protein Structure, Secondary; D017386:Sequence Homology, Amino Acid; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases; D014779:Virus Replication / Q000502:physiology*
chemical_list: D000090103:Antiviral Restriction Factors; D036022:Capsid Proteins; D002352:Carrier Proteins; D000070584:Tripartite Motif Proteins; C477346:TRIM5 protein, human; D044767:Ubiquitin-Protein Ligases