title: Translation of HLA-HIV associations to the cellular level: HIV adapts to inflate CD8 T cell responses against Nef and HLA-adapted variant epitopes.
abstract: Strong statistical associations between polymorphisms in HIV-1 population sequences and carriage of HLA class I alleles have been widely used to identify possible sites of CD8 T cell immune selection in vivo. However, there have been few attempts to prospectively and systematically test these genetic hypotheses arising from population-based studies at a cellular, functional level. We assayed CD8 T cell epitope-specific IFN-γ responses in 290 individuals from the same cohort, which gave rise to 874 HLA-HIV associations in genetic analyses, taking into account autologous viral sequences and individual HLA genotypes. We found immunological evidence for 58% of 374 associations tested as sites of primary immune selection and identified up to 50 novel HIV-1 epitopes using this reverse-genomics approach. Many HLA-adapted epitopes elicited equivalent or higher-magnitude IFN-γ responses than did the nonadapted epitopes, particularly in Nef. At a population level, inclusion of all of the immunoreactive variant CD8 T cell epitopes in Gag, Pol, Nef, and Env suggested that HIV adaptation leads to an inflation of Nef-directed immune responses relative to other proteins. We concluded that HLA-HIV associations mark viral epitopes subject to CD8 T cell selection. These results can be used to guide functional studies of specific epitopes and escape mutations, as well as to test, train, and evaluate analytical models of viral escape and fitness. The inflation of Nef and HLA-adapted variant responses may have negative effects on natural and vaccine immunity against HIV and, therefore, has implications for diversity coverage approaches in HIV vaccine design.
authors.affiliation: Centre for Clinical Immunology and Biomedical Statistics, Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia 6150, Australia.
authors.forename: Coral-Ann M
authors.initials: CA
authors.lastname: Almeida
authors.forename: Corine
authors.initials: C
authors.lastname: Bronke
authors.forename: Steven G
authors.initials: SG
authors.lastname: Roberts
authors.forename: Elizabeth
authors.initials: E
authors.lastname: McKinnon
authors.forename: Niamh M
authors.initials: NM
authors.lastname: Keane
authors.forename: Abha
authors.initials: A
authors.lastname: Chopra
authors.forename: Carl
authors.initials: C
authors.lastname: Kadie
authors.forename: Jonathan
authors.initials: J
authors.lastname: Carlson
authors.forename: David W
authors.initials: DW
authors.lastname: Haas
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Riddler
authors.forename: Richard
authors.initials: R
authors.lastname: Haubrich
authors.forename: David
authors.initials: D
authors.lastname: Heckerman
authors.forename: Simon
authors.initials: S
authors.lastname: Mallal
authors.forename: Mina
authors.initials: M
authors.lastname: John
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D015331:Cohort Studies; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005838:Genotype; D015658:HIV Infections / Q000235:genetics* / Q000276:immunology; D015497:HIV-1 / Q000235:genetics* / Q000276:immunology; D006680:HLA Antigens / Q000235:genetics*; D006801:Humans; D057131:Immune Evasion / Q000235:genetics; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D011110:Polymorphism, Genetic; D016032:Randomized Controlled Trials as Topic; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000276:immunology*
chemical_list: D018984:Epitopes, T-Lymphocyte; D006680:HLA Antigens; D054311:nef Gene Products, Human Immunodeficiency Virus; D007371:Interferon-gamma