title: HLA-A*68:02-restricted Gag-specific cytotoxic T lymphocyte responses can drive selection pressure on HIV but are subdominant and ineffective.
abstract: BACKGROUND
  Human leukocyte allele (HLA) class I polymorphism has the greatest impact of human genetic variation on viral load set point. A substantial part of this effect is due to the action of HLA-B and HLA-C alleles. With few exceptions the role of HLA-A molecules in immune control of HIV is unclear.
  
  
  METHODS
  We here study HLA-A*68:02, one of the most highly prevalent HLA-A alleles in C-clade infected sub-Saharan African populations, and one that plays a prominent role in the HIV-specific CD8 T-cell responses made against the virus.
  
  
  RESULTS
  We define eight epitopes restricted by this allele and propose the peptide binding motif for HLA-A*68:02. Although one of these epitopes almost exactly overlaps an HLA-B*57-restricted epitope in Gag linked with immune control of HIV, this HLA-A*68:02-restricted Gag-TA10 response imposed only weak selection pressure on the virus and was not associated with significantly lower viral setpoint. The only HLA-A*68:02-restricted responses imposing strong selection pressure on HIV were in the flanking regions of Pol-EA8 and Pol-EA11 and within the Vpr-EV10 epitope (P  =  8 × 10). However, targeting of this latter epitope was associated with significantly higher viral loads (P  =  0.003), suggesting lack of efficacy.
  
  
  CONCLUSIONS
  This study is consistent with previous data showing that HLA-A-restricted Gag-specific responses can impose selection pressure on HIV. In the case of HLA-A*68:02 the Gag response is subdominant, and apparently has little impact in natural infection. However, these data suggest the potential for high frequency vaccine-induced Gag responses restricted by this allele to have significant antiviral efficacy in vaccine recipients.
authors.affiliation: Department of Paediatrics, University of Oxford, Oxford, UK. henrik.kloverpris@k-rith.org
authors.forename: Henrik N
authors.initials: HN
authors.lastname: Kløverpris
authors.forename: Anette
authors.initials: A
authors.lastname: Stryhn
authors.forename: Mikkel
authors.initials: M
authors.lastname: Harndahl
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Carlson
authors.forename: Alasdair J
authors.initials: AJ
authors.lastname: Leslie
authors.forename: Fabian
authors.initials: F
authors.lastname: Chen
authors.forename: Lynn
authors.initials: L
authors.lastname: Riddell
authors.forename: Joseph
authors.initials: J
authors.lastname: Mulenga
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
authors.forename: Thumbi
authors.initials: T
authors.lastname: Ndung'u
authors.forename: Søren
authors.initials: S
authors.lastname: Buus
authors.forename: Philip
authors.initials: P
authors.lastname: Goulder
mesh_terms: D017954:Africa South of the Sahara; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D000939:Epitopes / Q000276:immunology; D006678:HIV / Q000235:genetics* / Q000276:immunology*; D015234:HLA-A Antigens / Q000276:immunology*; D006801:Humans; D028861:Nuclear Pore Complex Proteins; D012641:Selection, Genetic; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000276:immunology*
chemical_list: D000939:Epitopes; D015234:HLA-A Antigens; C053029:HLA-A*68 antigen; C085914:NUP214 protein, human; D028861:Nuclear Pore Complex Proteins; D054301:gag Gene Products, Human Immunodeficiency Virus