title: Association between a naturally arising polymorphism within a functional region of HIV-1 Nef and disease progression in chronic HIV-1 infection.
abstract: HIV-1 Nef mediates downregulation of HLA class I (HLA-I) through a number of highly conserved sequence motifs. We investigated the in vivo implication(s) of naturally arising polymorphisms in functional motifs in HIV-1 Nef that are associated with HLA-I downregulation, including the acidic cluster, polyproline, di-arginine and Met-20 regions. Plasma samples from treatment-naive, chronically HIV-1 infected subjects were collected after obtaining informed consent, and viral RNA was extracted and amplified by nested RT-PCR. The resultant nef amplicons were sequenced directly, and subtype-B sequences with an intact open reading frame (n = 406) were included in our analyses. There was over-representation of isoleucine at position 20 (Ile-20) in our dataset when compared to sequences in the Los Alamos sequence database (17.7 vs. 6.9 %, p = 0.0309). The presence of having Ile-20 in Nef was found to be associated with higher median plasma viral load (p = 0.013), independent of associated codons or viral lineage effects, whereas no clinical association was found with polymorphisms in the other functional motifs. Moreover, introduction of a Met-20-to-Ile mutation in a laboratory strain SF2 Nef resulted in a modest, albeit not statistically significant, increase in HLA class I downregulation activity (p = 0.06). Taken together, we have identified a naturally arising polymorphism, Ile-20, within HIV-1 subtype B Nef that is associated with poorer disease outcome.
authors.affiliation: Center for AIDS Research, Kumamoto University, 2-2-1 Chuo-ku, Honjo, Kumamoto, 860-0811, Japan.
authors.forename: Stanley C
authors.initials: SC
authors.lastname: Meribe
authors.forename: Zafrul
authors.initials: Z
authors.lastname: Hasan
authors.forename: Macdonald
authors.initials: M
authors.lastname: Mahiti
authors.forename: Francis
authors.initials: F
authors.lastname: Mwimanzi
authors.forename: Mako
authors.initials: M
authors.lastname: Toyoda
authors.forename: Masahiko
authors.initials: M
authors.lastname: Mori
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Gatanaga
authors.forename: Tadashi
authors.initials: T
authors.lastname: Kikuchi
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Miura
authors.forename: Ai
authors.initials: A
authors.lastname: Kawana-Tachikawa
authors.forename: Aikichi
authors.initials: A
authors.lastname: Iwamoto
authors.forename: Shinichi
authors.initials: S
authors.lastname: Oka
authors.forename: Takamasa
authors.initials: T
authors.lastname: Ueno
mesh_terms: D000328:Adult; D002908:Chronic Disease; D018450:Disease Progression; D015536:Down-Regulation; D005260:Female; D015658:HIV Infections / Q000235:genetics / Q000276:immunology / Q000821:virology*; D015497:HIV-1 / Q000145:classification / Q000235:genetics* / Q000302:isolation & purification / Q000502:physiology; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D010802:Phylogeny; D011110:Polymorphism, Genetic; D019562:Viral Load; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000235:genetics* / Q000378:metabolism
chemical_list: D015395:Histocompatibility Antigens Class I; D054311:nef Gene Products, Human Immunodeficiency Virus