title: Adaptation of HIV-1 to its human host.
abstract: Human immunodeficiency virus type 1 (HIV-1) originated from three independent cross-species transmissions of simian immunodeficiency virus (SIVcpzPtt) infecting chimpanzees (Pan troglodytes troglodytes) in west central Africa, giving rise to pandemic (group M) and non-pandemic (groups N and O) clades of HIV-1. To identify host-specific adaptations in HIV-1 we compared the inferred ancestral sequences of HIV-1 groups M, N and O to 12 full length genome sequences of SIVcpzPtt and four of the outlying but closely related SIVcpzPts (from P. t. schweinfurthii). This analysis revealed a single site that was completely conserved among SIVcpzPtt strains but different (due to the same change) in all three groups of HIV-1. This site, Gag-30, lies within p17, the gag-encoded matrix protein. It is Met in SIVcpzPtt, underwent a conservative replacement by Leu in one lineage of SIVcpzPts but changed radically to Arg on all three lineages leading to HIV-1. During subsequent diversification this site has been conserved as a basic residue (Arg or Lys) in most lineages of HIV-1. Retrospective analysis revealed that Gag-30 had reverted to Met in a previous experiment in which HIV-1 was passaged through chimpanzees. To examine whether this substitution conferred a species specific growth advantage, we used site-directed mutagenesis to generate variants of these chimpanzee-adapted HIV-1 strains with Lys at Gag-30, and tested their replication in both human and chimpanzee CD4+ T lymphocytes. Remarkably, viruses encoding Met replicated to higher titers than viruses encoding Lys in chimpanzee T cells, but the opposite was found in human T cells. Taken together, these observations provide compelling evidence for host-specific adaptation during the emergence of HIV-1 and identify the viral matrix protein as a modulator of viral fitness following transmission to the new human host.
authors.affiliation: Institute of Genetics, University of Nottingham, Queens Medical Centre, Nottingham, UK.
authors.forename: Louise V
authors.initials: LV
authors.lastname: Wain
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Bailes
authors.forename: Frederic
authors.initials: F
authors.lastname: Bibollet-Ruche
authors.forename: Julie M
authors.initials: JM
authors.lastname: Decker
authors.forename: Brandon F
authors.initials: BF
authors.lastname: Keele
authors.forename: Fran
authors.initials: F
authors.lastname: Van Heuverswyn
authors.forename: Yingying
authors.initials: Y
authors.lastname: Li
authors.forename: Jun
authors.initials: J
authors.lastname: Takehisa
authors.forename: Eitel Mpoudi
authors.initials: EM
authors.lastname: Ngole
authors.forename: George M
authors.initials: GM
authors.lastname: Shaw
authors.forename: Martine
authors.initials: M
authors.lastname: Peeters
authors.forename: Beatrice H
authors.initials: BH
authors.lastname: Hahn
authors.forename: Paul M
authors.initials: PM
authors.lastname: Sharp
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000453:epidemiology / Q000635:transmission* / Q000821:virology; D000350:Africa, Central; D000818:Animals; D005075:Biological Evolution; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000821:virology; D015683:Gene Products, gag / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D016297:Mutagenesis, Site-Directed; D009154:Mutation / Q000235:genetics; D002679:Pan troglodytes; D010802:Phylogeny; D017422:Sequence Analysis, DNA; D016097:Simian Acquired Immunodeficiency Syndrome / Q000453:epidemiology / Q000635:transmission* / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000145:classification* / Q000235:genetics / Q000302:isolation & purification; D014779:Virus Replication
chemical_list: D015683:Gene Products, gag