title: CTL-mediated selective pressure influences dynamic evolution and pathogenic functions of HIV-1 Nef.
abstract: HIV-1 Nef plays multiple roles in modulating immune responses, even though it is a dominant CTL target itself. How Nef accomplishes the balance between such conflicting selective pressures remains elusive. By genetic and functional studies, we found that Arg75Thr and Tyr85Phe mutations, located in a well-conserved proline-rich region in Nef, were differently associated with escape from CTL responses specific for two overlapping HLA-B35-restricted epitopes. CTLs specific for an epitope, that selected Tyr85Phe, were elicited earlier and had more potent functional avidities than did those that selected Arg75Thr. Although the double mutant could escape from both CTLs, the mutations are rarely observed in combination naturally. Introduction of both mutations reduced Nef's HLA class I down-regulation activity and increased the susceptibility of virus-infected cells to recognition by CTLs targeting other epitopes. Moreover, the mutant Nef was impaired in the association with activated cellular kinases and in the enhancement of viral replication. These results highlight CTL immunosurveillance as important modulators of Nef's biological activity in the infected host.
authors.affiliation: Division of Viral Immunology, Center for AIDS Research, Kumamoto University, Kumamoto, Japan. uenotaka@kumamoto-u.ac.jp
authors.forename: Takamasa
authors.initials: T
authors.lastname: Ueno
authors.forename: Chihiro
authors.initials: C
authors.lastname: Motozono
authors.forename: Sachi
authors.initials: S
authors.lastname: Dohki
authors.forename: Philip
authors.initials: P
authors.lastname: Mwimanzi
authors.forename: Susanne
authors.initials: S
authors.lastname: Rauch
authors.forename: Oliver T
authors.initials: OT
authors.lastname: Fackler
authors.forename: Shinichi
authors.initials: S
authors.lastname: Oka
authors.forename: Masafumi
authors.initials: M
authors.lastname: Takiguchi
mesh_terms: D000595:Amino Acid Sequence; D000940:Antigenic Variation / Q000235:genetics; D015536:Down-Regulation; D018604:Epitope Mapping; D019143:Evolution, Molecular; D005260:Female; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1; D015797:HLA-B35 Antigen / Q000276:immunology; D006801:Humans; D007157:Immunologic Surveillance; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D011971:Receptors, Immunologic; D012641:Selection, Genetic; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D054462:p21-Activated Kinases / Q000378:metabolism
chemical_list: D015797:HLA-B35 Antigen; D011971:Receptors, Immunologic; D054311:nef Gene Products, Human Immunodeficiency Virus; D054462:p21-Activated Kinases