title: Temporal association of HLA-B*81:01- and HLA-B*39:10-mediated HIV-1 p24 sequence evolution with disease progression.
abstract: HLA-B*81:01 and HLA-B*39:10 alleles have been associated with viremic control in HIV-1 subtype C infection. Both alleles restrict the TL9 epitope in p24 Gag, and cytotoxic-T-lymphocyte (CTL)-mediated escape mutations in this epitope have been associated with an in vitro fitness cost to the virus. We investigated the timing and impact of mutations in the TL9 epitope on disease progression in five B*81:01- and two B*39:10-positive subtype C-infected individuals. Whereas both B*39:10 participants sampled at 2 months postinfection had viruses with mutations in the TL9 epitope, in three of the five (3/5) B*81:01 participants, TL9 escape mutations were only detected 10 months after infection, taking an additional 10 to 15 months to reach fixation. In the two remaining B*81:01 individuals, one carried a TL9 escape variant at 2 weeks postinfection, whereas no escape mutations were detected in the virus from the other participant for up to 33 months postinfection, despite CTL targeting of the epitope. In all participants, escape mutations in TL9 were linked to coevolving residues in the region of Gag known to be associated with host tropism. Late escape in TL9, together with coevolution of putative compensatory mutations, coincided with a spontaneous increase in viral loads in two individuals who were otherwise controlling the infection. These results provide in vivo evidence of the detrimental impact of B*81:01-mediated viral evolution, in a single Gag p24 epitope, on the control of viremia.
authors.affiliation: Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: R S
authors.initials: RS
authors.lastname: Ntale
authors.forename: D R
authors.initials: DR
authors.lastname: Chopera
authors.forename: N K
authors.initials: NK
authors.lastname: Ngandu
authors.forename: D
authors.initials: D
authors.lastname: Assis de Rosa
authors.forename: L
authors.initials: L
authors.lastname: Zembe
authors.forename: H
authors.initials: H
authors.lastname: Gamieldien
authors.forename: M
authors.initials: M
authors.lastname: Mlotshwa
authors.forename: L
authors.initials: L
authors.lastname: Werner
authors.forename: Z
authors.initials: Z
authors.lastname: Woodman
authors.forename: K
authors.initials: K
authors.lastname: Mlisana
authors.forename: S
authors.initials: S
authors.lastname: Abdool Karim
authors.forename: C M
authors.initials: CM
authors.lastname: Gray
authors.forename: C
authors.initials: C
authors.lastname: Williamson
mesh_terms: D000483:Alleles; D002469:Cell Separation; D018450:Disease Progression; D000939:Epitopes / Q000737:chemistry; D005260:Female; D005434:Flow Cytometry; D005838:Genotype; D016655:HIV Core Protein p24 / Q000235:genetics*; D015658:HIV Infections / Q000235:genetics / Q000276:immunology* / Q000821:virology*; D015497:HIV-1 / Q000378:metabolism*; D015235:HLA-B Antigens / Q000235:genetics*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007700:Kinetics; D008137:Longitudinal Studies; D008969:Molecular Sequence Data; D009154:Mutation; D013019:South Africa; D013997:Time Factors; D051217:Toll-Like Receptor 9 / Q000235:genetics
chemical_list: D000939:Epitopes; D016655:HIV Core Protein p24; D015235:HLA-B Antigens; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; D007371:Interferon-gamma