title: HLA-Cw*03-restricted CD8+ T-cell responses targeting the HIV-1 gag major homology region drive virus immune escape and fitness constraints compensated for by intracodon variation.
abstract: The potential importance of HLA-C-restricted CD8+ cytotoxic T lymphocytes (CTL) in HIV infection remains undetermined. We studied the dominant HLA-Cw*03-restricted CTL response to YVDRFFKTL(296-304) (YL9), within the conserved major homology region (MHR) of the Gag protein, in 80 HLA-Cw*03-positive individuals with chronic HIV infection to better define the efficacy of the YL9 HLA-C-restricted response. The HLA-Cw*03 allele is strongly associated with HIV sequence changes from Thr-303 to Val, Ile, or Ala at position 8 within the YL9 epitope (P=1.62×10(-10)). In vitro studies revealed that introduction of the changes T303I and T303A into the YL9 epitope both significantly reduced CTL recognition and substantially reduced the viral replicative capacity. However, subsequent selection of the Val-303 variant, via intracodon variation from Ile-303 (I303V) or Ala-303 (A303V), restored both viral fitness and CTL recognition, as supported by our in vivo data. These results illustrate that HLA-C-restricted CTL responses are capable of driving viral immune escape within Gag, but in contrast to what was previously described for HLA-B-restricted Gag escape mutants, the common Cw*03-Gag-303V variant selected resulted in no detectable benefit to the host.
authors.affiliation: Department of Paediatrics, Peter Medawar Building for Pathogen Research, South Parks Road, Oxford OX1 3SY, United Kingdom.
authors.forename: Isobella
authors.initials: I
authors.lastname: Honeyborne
authors.forename: Francisco M
authors.initials: FM
authors.lastname: Codoñer
authors.forename: Alasdair
authors.initials: A
authors.lastname: Leslie
authors.forename: Gareth
authors.initials: G
authors.lastname: Tudor-Williams
authors.forename: Graz
authors.initials: G
authors.lastname: Luzzi
authors.forename: Thumbi
authors.initials: T
authors.lastname: Ndung'u
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Goulder
authors.forename: Julia G
authors.initials: JG
authors.lastname: Prado
mesh_terms: D019943:Amino Acid Substitution; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D015658:HIV Infections; D015497:HIV-1 / Q000276:immunology*; D015236:HLA-C Antigens / Q000276:immunology*; D054884:Host-Pathogen Interactions; D006801:Humans; D057131:Immune Evasion; D019169:Jurkat Cells; D010446:Peptide Fragments / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic; D014779:Virus Replication; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000276:immunology*
chemical_list: D015236:HLA-C Antigens; D010446:Peptide Fragments; D054301:gag Gene Products, Human Immunodeficiency Virus