title: Modulation of the severe CD4+ T-cell loss caused by a pathogenic simian-human immunodeficiency virus by replacement of the subtype B vpu with the vpu from a subtype C HIV-1 clinical isolate.
abstract: Previously, we showed that the Vpu protein from subtype C human immunodeficiency virus type 1 (HIV-1) was efficiently targeted to the cell surface, suggesting that this protein has biological properties that differ from the well-studied subtype B Vpu protein. In this study, we have further analyzed the biological properties of the subtype C Vpu protein. Flow cytometric analysis revealed that the subtype B Vpu (strain HXB2) was more efficient at down-regulating CD4 surface expression than the Vpu proteins from four subtype C clinical isolates. We constructed a simian-human immunodeficiency virus virus, designated as SHIV(SCVpu), in which the subtype B vpu gene from the pathogenic SHIV(KU-1bMC33) was substituted with the vpu from a clinical isolate of subtype C HIV-1 (strain C.96.BW16B01). Cell culture studies revealed that SHIV(SCVpu) replicated with slightly reduced kinetics when compared with the parental SHIV(KU-1bMC33) and that the viral Env and Gag precursor proteins were synthesized and processed similarly compared to the parental SHIV(KU-1bMC33). To determine if substitution of the subtype C Vpu protein affected the pathogenesis of the virus, three pig-tailed macaques were inoculated with SHIV(SCVpu) and circulating CD4+ T-cell levels and viral loads were monitored for up to 44 weeks. Our results show that SHIV(SCVpu) caused a more gradual decline in the rate of CD4+ T cells in pig-tailed macaques compared to those inoculated with parental subtype B SHIV(KU-1bMC33). These results show for the first time that different Vpu proteins of HIV-1 can influence the rate at which CD4+ T-cell loss occurs in the SHIV/pig-tailed macaque model.
authors.affiliation: Department of Anatomy and Cell Biology, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA.
authors.forename: M Sarah
authors.initials: MS
authors.lastname: Hill
authors.forename: Autumn
authors.initials: A
authors.lastname: Ruiz
authors.forename: Erik
authors.initials: E
authors.lastname: Pacyniak
authors.forename: David M
authors.initials: DM
authors.lastname: Pinson
authors.forename: Nathan
authors.initials: N
authors.lastname: Culley
authors.forename: Bonnie
authors.initials: B
authors.lastname: Yen
authors.forename: Scott W
authors.initials: SW
authors.lastname: Wong
authors.forename: Edward B
authors.initials: EB
authors.lastname: Stephens
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000648:ultrastructure; D002460:Cell Line; D004195:Disease Models, Animal; D005434:Flow Cytometry; D005456:Fluorescent Dyes / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000276:immunology / Q000472:pathogenicity*; D006367:HeLa Cells; D054298:Human Immunodeficiency Virus Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D006801:Humans; D018655:Lymphocyte Count; D008254:Macaca nemestrina; D008969:Molecular Sequence Data; D010957:Plasmids; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015302:Simian Immunodeficiency Virus; D013601:T-Lymphocytes / Q000648:ultrastructure / Q000821:virology; D013997:Time Factors; D014162:Transfection; D019562:Viral Load; D054334:Viral Regulatory and Accessory Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D000086082:Viroporin Proteins
chemical_list: D005456:Fluorescent Dyes; D049452:Green Fluorescent Proteins; D054298:Human Immunodeficiency Virus Proteins; D011993:Recombinant Fusion Proteins; D054334:Viral Regulatory and Accessory Proteins; C485184:enhanced green fluorescent protein; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins