title: Generation of rhesus macaque-tropic HIV-1 clones that are resistant to major anti-HIV-1 restriction factors.
abstract: Human immunodeficiency virus type 1 (HIV-1) replication in macaque cells is restricted mainly by antiviral cellular APOBEC3, TRIM5α/TRIM5CypA, and tetherin proteins. For basic and clinical HIV-1/AIDS studies, efforts to construct macaque-tropic HIV-1 (HIV-1mt) have been made by us and others. Although rhesus macaques are commonly and successfully used as infection models, no HIV-1 derivatives suitable for in vivo rhesus research are available to date. In this study, to obtain novel HIV-1mt clones that are resistant to major restriction factors, we altered Gag and Vpu of our best HIV-1mt clone described previously. First, by sequence- and structure-guided mutagenesis, three amino acid residues in Gag-capsid (CA) (M94L/R98S/G114Q) were found to be responsible for viral growth enhancement in a macaque cell line. Results of in vitro TRIM5α susceptibility testing of HIV-1mt carrying these substitutions correlated well with the increased viral replication potential in macaque peripheral blood mononuclear cells (PBMCs) with different TRIM5 alleles, suggesting that the three amino acids in HIV-1mt CA are involved in the interaction with TRIM5α. Second, we replaced the transmembrane domain of Vpu of this clone with the corresponding region of simian immunodeficiency virus SIVgsn166 Vpu. The resultant clone, MN4/LSDQgtu, was able to antagonize macaque but not human tetherin, and its Vpu effectively functioned during viral replication in a macaque cell line. Notably, MN4/LSDQgtu grew comparably to SIVmac239 and much better than any of our other HIV-1mt clones in rhesus macaque PBMCs. In sum, MN4/LSDQgtu is the first HIV-1 derivative that exhibits resistance to the major restriction factors in rhesus macaque cells.
authors: Department of Microbiology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Tokushima, Japan.
authors: Masako
authors: M
authors: Nomaguchi
authors: Masaru
authors: M
authors: Yokoyama
authors: Ken
authors: K
authors: Kono
authors: Emi E
authors: EE
authors: Nakayama
authors: Tatsuo
authors: T
authors: Shioda
authors: Naoya
authors: N
authors: Doi
authors: Sachi
authors: S
authors: Fujiwara
authors: Akatsuki
authors: A
authors: Saito
authors: Hirofumi
authors: H
authors: Akari
authors: Kei
authors: K
authors: Miyakawa
authors: Akihide
authors: A
authors: Ryo
authors: Hirotaka
authors: H
authors: Ode
authors: Yasumasa
authors: Y
authors: Iwatani
authors: Tomoyuki
authors: T
authors: Miura
authors: Tatsuhiko
authors: T
authors: Igarashi
authors: Hironori
authors: H
authors: Sato
authors: Akio
authors: A
authors: Adachi
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D015683:Gene Products, gag / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D054298:Human Immunodeficiency Virus Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000821:virology; D008253:Macaca mulatta / Q000821:virology*; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D054334:Viral Regulatory and Accessory Proteins / Q000235:genetics / Q000378:metabolism; D056189:Viral Tropism; D014779:Virus Replication; D000086082:Viroporin Proteins
chemical_list: D015683:Gene Products, gag; D054298:Human Immunodeficiency Virus Proteins; D050505:Mutant Proteins; D054334:Viral Regulatory and Accessory Proteins; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins
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