title: Distinct combinations of amino acid substitutions in N-terminal domain of Gag-capsid afford HIV-1 resistance to rhesus TRIM5α.
abstract: TRIM5α is a potent anti-retroviral factor that interacts with viral capsid (CA) in a species-specific manner. Recently, we and others reported generation of two distinct HIV-1 CAs that effectively overcome rhesus TRIM5α-imposed species barrier. In this study, to directly compare the effect of different mutations in the two HIV-1 CAs on evasion from macaque TRIM5-restriction, we newly generated macaque-tropic HIV-1 (HIV-1mt) proviral clones carrying the distinct CAs in the same genomic backbone, and examined their replication abilities in macaque TRIM5-overexpressing human cells and in rhesus cells. Comparative analysis of amino acid sequences and homology modeling-based structures revealed that, while both CAs gained some mutated amino acids with similar physicochemical properties, their overall appearances of N-terminal domains were different. Experimentally, the two CAs exhibited incomplete TRIM5α-resistance relative to SIVmac239 CA and different degrees of susceptibility to various TRIM5 proteins. Finally, two HIV-1mt clones carrying a different combination of the CA mutations were found to grow to a comparable extent in established and primary rhesus cells. Our data show that there could be some distinct CA patterns to confer significant TRIM5-resistance on HIV-1.
authors.affiliation: Department of Microbiology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Tokushima, Japan.
authors.forename: Masako
authors.initials: M
authors.lastname: Nomaguchi
authors.affiliation: Department of Viral Infections, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
authors.forename: Emi E
authors.initials: EE
authors.lastname: Nakayama
authors.affiliation: Laboratory of Viral Genomics, Pathogen Genomics Center, National Institute of Infectious Diseases, Musashimurayama, Tokyo, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Yokoyama
authors.affiliation: Department of Microbiology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Tokushima, Japan; Japanese Foundation for AIDS Prevention, Chiyoda-ku, Tokyo, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Doi
authors.affiliation: Laboratory of Primate Model, Experimental Research Center for Infectious Diseases, Institute for Virus Research, Kyoto University, Kyoto, Kyoto, Japan.
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Igarashi
authors.affiliation: Department of Viral Infections, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Shioda
authors.affiliation: Laboratory of Viral Genomics, Pathogen Genomics Center, National Institute of Infectious Diseases, Musashimurayama, Tokyo, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Sato
authors.affiliation: Department of Microbiology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Tokushima, Japan. Electronic address: adachi@basic.med.tokushima-u.ac.jp.
authors.forename: Akio
authors.initials: A
authors.lastname: Adachi
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D036022:Capsid Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D008253:Macaca mulatta; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases; D056189:Viral Tropism; D014779:Virus Replication; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics* / Q000378:metabolism
chemical_list: D036022:Capsid Proteins; D050505:Mutant Proteins; D011506:Proteins; D054301:gag Gene Products, Human Immunodeficiency Virus; C482587:TRIM5(alpha) protein, rhesus monkey; D044767:Ubiquitin-Protein Ligases
keywords: Capsid; Gag-CA; HIV-1; HIV-1mt; Rhesus macaque; TRIM5α