title: HIV-infected sex workers with beneficial HLA-variants are potential hubs for selection of HIV-1 recombinants that may affect disease progression.
abstract: Cytotoxic T lymphocyte (CTL) responses against the HIV Gag protein are associated with lowering viremia; however, immune control is undermined by viral escape mutations. The rapid viral mutation rate is a key factor, but recombination may also contribute. We hypothesized that CTL responses drive the outgrowth of unique intra-patient HIV-recombinants (URFs) and examined gag sequences from a Kenyan sex worker cohort. We determined whether patients with HLA variants associated with effective CTL responses (beneficial HLA variants) were more likely to carry URFs and, if so, examined whether they progressed more rapidly than patients with beneficial HLA-variants who did not carry URFs. Women with beneficial HLA-variants (12/52) were more likely to carry URFs than those without beneficial HLA variants (3/61) (p < 0.0055; odds ratio = 5.7). Beneficial HLA variants were primarily found in slow/standard progressors in the URF group, whereas they predominated in long-term non-progressors/survivors in the remaining cohort (p = 0.0377). The URFs may sometimes spread and become circulating recombinant forms (CRFs) of HIV and local CRF fragments were over-represented in the URF sequences (p < 0.0001). Collectively, our results suggest that CTL-responses associated with beneficial HLA variants likely drive the outgrowth of URFs that might reduce the positive effect of these CTL responses on disease progression.
authors.affiliation: Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Chih-Hao
authors.initials: CH
authors.lastname: Chang
authors.affiliation: Department of Zoology, University of Oxford, South Parks Road, Oxford, United Kingdom.
authors.forename: Nicolaas C
authors.initials: NC
authors.lastname: Kist
authors.affiliation: National HIV and Retrovirology Laboratories, JC Wilt Infectious Disease Research Centre, Winnipeg, Manitoba, Canada.
authors.forename: Tammy L
authors.initials: TL
authors.lastname: Stuart Chester
authors.affiliation: Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Vattipally B
authors.initials: VB
authors.lastname: Sreenu
authors.affiliation: Department of Medical Microbiology, University of Manitoba, Winnipeg, MB, Canada.
authors.forename: Melissa
authors.initials: M
authors.lastname: Herman
authors.affiliation: 1] National HIV and Retrovirology Laboratories, JC Wilt Infectious Disease Research Centre, Winnipeg, Manitoba, Canada [2] Department of Medical Microbiology, University of Manitoba, Winnipeg, MB, Canada.
authors.forename: Ma
authors.initials: M
authors.lastname: Luo
authors.affiliation: Department of Statistics, University of Oxford, Oxford, United Kingdom.
authors.forename: Daniel
authors.initials: D
authors.lastname: Lunn
authors.affiliation: Office of the Regius Professor of Medicine, The Richard Doll Building, University of Oxford, Oxford, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Bell
authors.affiliation: Department of Medical Microbiology, University of Manitoba, Winnipeg, MB, Canada.
authors.forename: Francis A
authors.initials: FA
authors.lastname: Plummer
authors.affiliation: 1] National HIV and Retrovirology Laboratories, JC Wilt Infectious Disease Research Centre, Winnipeg, Manitoba, Canada [2] Department of Medical Microbiology, University of Manitoba, Winnipeg, MB, Canada [3] Department of Immunology, University of Manitoba, Winnipeg, MB, Canada.
authors.forename: T Blake
authors.initials: TB
authors.lastname: Ball
authors.affiliation: Department of Zoology, University of Oxford, South Parks Road, Oxford, United Kingdom.
authors.forename: Aris
authors.initials: A
authors.lastname: Katzourakis
authors.affiliation: 1] Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom [2] Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Astrid K N
authors.initials: AK
authors.lastname: Iversen
mesh_terms: D000328:Adult; D018450:Disease Progression; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D016655:HIV Core Protein p24 / Q000235:genetics; D015658:HIV Infections / Q000821:virology*; D015497:HIV-1 / Q000235:genetics*; D006680:HLA Antigens / Q000235:genetics; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000821:virology; D058889:Molecular Typing; D009154:Mutation; D011995:Recombination, Genetic; D060386:Sex Workers; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics
chemical_list: D016655:HIV Core Protein p24; D006680:HLA Antigens; D054301:gag Gene Products, Human Immunodeficiency Virus