title: Dynamic range of Nef functions in chronic HIV-1 infection.
abstract: HIV-1 Nef is required for efficient viral replication and pathogenesis. However, the extent to which Nef's functions are maintained in natural sequences during chronic infection, and their clinical relevance, remains incompletely characterized. Relative to a control Nef from HIV-1 strain SF2, HLA class I and CD4 down-regulation activities of 46 plasma RNA Nef sequences derived from unique chronic infected individuals were generally high and displayed narrow dynamic ranges, whereas Nef-mediated virion infectivity, PBMC replication and CD74 up-regulation exhibited broader dynamic ranges. 80% of patient-derived Nefs were active for at least three functions examined. Functional co-dependencies were identified, including positive correlations between CD4 down-regulation and virion infectivity, replication, and CD74 up-regulation, and between CD74 up-regulation and PBMC replication. Nef-mediated virion infectivity inversely correlated with patient CD4(±) T-cell count. Strong functional co-dependencies and the polyfunctional nature of patient-derived Nef sequences suggest a phenotypic requirement to maintain multiple Nef functions during chronic infection.
authors.affiliation: Center for AIDS Research, Kumamoto University, Kumamoto, Japan.
authors.forename: Philip
authors.initials: P
authors.lastname: Mwimanzi
authors.forename: Tristan J
authors.initials: TJ
authors.lastname: Markle
authors.forename: Yoko
authors.initials: Y
authors.lastname: Ogata
authors.forename: Eric
authors.initials: E
authors.lastname: Martin
authors.forename: Michiyo
authors.initials: M
authors.lastname: Tokunaga
authors.forename: Macdonald
authors.initials: M
authors.lastname: Mahiti
authors.forename: Xiaomei T
authors.initials: XT
authors.lastname: Kuang
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
authors.forename: Mark A
authors.initials: MA
authors.lastname: Brockman
authors.forename: Zabrina L
authors.initials: ZL
authors.lastname: Brumme
authors.forename: Takamasa
authors.initials: T
authors.lastname: Ueno
mesh_terms: D000944:Antigens, Differentiation, B-Lymphocyte / Q000096:biosynthesis; D018791:CD4 Lymphocyte Count; D015658:HIV Infections / Q000821:virology*; D015497:HIV-1 / Q000472:pathogenicity*; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000821:virology; D015854:Up-Regulation; D037521:Virulence Factors / Q000378:metabolism*; D014779:Virus Replication; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D000949:Histocompatibility Antigens Class II; D037521:Virulence Factors; C045084:invariant chain; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1