title: Naturally arising HIV-1 Nef variants conferring escape from cytotoxic T lymphocytes influence viral entry co-receptor expression and susceptibility to superinfection.
abstract: HIV-1 Nef is a key factor for pathogenesis and is known to down-regulate functionally important molecules, including viral entry co-receptor CCR5 and CXCR4, from the surface of HIV-infected cells. Some of these Nef activities are mediated by the well-conserved proline-rich region of Nef, and this region is highly targeted by cytotoxic T lymphocytes (CTLs). In the present study, we asked whether Nef variants selected under CTL-mediated selective pressure in vivo may constrain these important Nef activities. The analysis of autologous nef sequences isolated from a cohort of total 235 subjects in Japan revealed that the subjects showing amino acid variations, such as Arg75Thr and Tyr85Phe, located within the proline-rich region were significantly over-represented by those having HLA-B*3501. CTL assays corroborated that these mutations conferred escape from HLA-B(∗)3501-restricted CTLs. The Arg75Thr variant Nef selectively impaired CCR5, but not CXCR4, down-regulation activity from the cell surface; whereas the Tyr85Phe variant Nef affected neither CCR5 nor CXCR4 down-regulation activity. Moreover, the cells expressing the Arg75Thr variant Nef significantly impaired protection from superinfection by CCR5-tropic, but not CXCR4-tropic, viruses. These results highlighted the importance of certain Nef-specific CTLs in modulation of viral co-receptor down-regulation activity and protection from HIV-1 superinfection, providing us with additional insight into vaccine design.
authors.affiliation: Center for AIDS Research, Kumamoto University, Kumamoto, Japan.
authors.forename: Philip
authors.initials: P
authors.lastname: Mwimanzi
authors.forename: Zafrul
authors.initials: Z
authors.lastname: Hasan
authors.forename: Michiyo
authors.initials: M
authors.lastname: Tokunaga
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Gatanaga
authors.forename: Shinichi
authors.initials: S
authors.lastname: Oka
authors.forename: Takamasa
authors.initials: T
authors.lastname: Ueno
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology; D019943:Amino Acid Substitution; D004252:DNA Mutational Analysis; D015536:Down-Regulation; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D015235:HLA-B Antigens / Q000276:immunology; D015797:HLA-B35 Antigen; D006801:Humans; D009154:Mutation; D019713:Receptors, CCR5 / Q000276:immunology; D019718:Receptors, CXCR4 / Q000276:immunology; D015163:Superinfection / Q000276:immunology* / Q000821:virology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000821:virology; D053586:Virus Internalization; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology*
chemical_list: D016915:AIDS Vaccines; C527276:CXCR4 protein, human; D015235:HLA-B Antigens; C500431:HLA-B*35:01 antigen; D015797:HLA-B35 Antigen; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D054311:nef Gene Products, Human Immunodeficiency Virus