title: Multilayered HIV-1 gag-specific T-cell responses contribute to slow progression in HLA-A*30-B*13-C*06-positive patients.
abstract: OBJECTIVE
  The HLA-A30-B13-C06 haplotype is reported to be associated with slow disease progression in the HIV-1-infected Northern Han Chinese population, but the mechanism remains unknown.
  
  
  METHODS
  Gag-specific T-cell responses and gag sequencing were performed in nine B' clade HIV-1-infected HLA-A30-B13-C06-positive slow progressors to understand HLA-associated viral control.
  
  
  METHODS
  Interferon-γ ELISPOT assays were performed to determine the Gag-specific T-cell responses and cross-reactivity to variant peptides. Longitudinal HIV-1 gag sequencing was performed at the clonal level.
  
  
  RESULTS
  The overlapping peptides (OLP)-48: RQANFLGKIWPSHKGRPGNF (RL42 Gag434-453); OLP-2: GQLDRWEKIRLRPGGKKKYR (RL42 Gag11-30); OLP-15: VQNLQGQMVHQPISPRTLNA (RL42 Gag135-154) and OLP-16: HQPISPRTLNAWVKVVEEKA (RL42 Gag144-163) were dominant in HLA-A30-B13-C06-positive patients. A new epitope [HQPISPRTL (Gag144-152, HL9)] within OLP-15 and OLP-16 was identified. Results showed that strong cross-reactive responses to multiple immunodominant peptides were associated with better clinical outcomes. In addition, efficient cross-recognition of HL9 autologous variants developed in patients was associated with high CD4 T-cell counts. However, two patients who had developed mutations to their dominant responses during the follow-up experienced decrease in CD4 T-cell counts. It appears that Gag-specific T-cell responses against one or more unmutated epitopes or cross-recognition of autologous epitope variants contribute to slow disease progression in HLA-A30-B13-C06-positive patients.
  
  
  CONCLUSIONS
  We conclude that a single 'appropriate' Gag-specific T-cell response appears to be sufficient to protect patients from disease progression. HLA-A30-B13-C06-positive individuals benefited from having a choice of numerous immunodominant gag epitopes for T cells to react. The study offers new insight for future design of T-cell-based HIV-1 vaccine.
authors.affiliation: aKey Laboratory of AIDS Immunology of National Health and Family Planning Commission, Department of Laboratory Medicine, The First Affiliated Hospital, China Medical University, Shenyang bCollaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou cCenter for Disease Control and Prevention of Henan Province, Zhengzhou, China dMedical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford University, Oxford, UK. *Hui Zhang and Hong Shang contributed equally to the writing of this article.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Xiaoxu
authors.initials: X
authors.lastname: Han
authors.forename: Bin
authors.initials: B
authors.lastname: Zhao
authors.forename: Minghui
authors.initials: M
authors.lastname: An
authors.forename: Zhe
authors.initials: Z
authors.lastname: Wang
authors.forename: Fanming
authors.initials: F
authors.lastname: Jiang
authors.forename: Junjie
authors.initials: J
authors.lastname: Xu
authors.forename: Zining
authors.initials: Z
authors.lastname: Zhang
authors.forename: Tao
authors.initials: T
authors.lastname: Dong
authors.forename: Hong
authors.initials: H
authors.lastname: Shang
mesh_terms: D000328:Adult; D044466:Asian People; D003429:Cross Reactions; D058501:Enzyme-Linked Immunospot Assay; D005260:Female; D015658:HIV Infections / Q000276:immunology*; D020276:HIV Long-Term Survivors; D006680:HLA Antigens / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D016056:Immunodominant Epitopes / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D017422:Sequence Analysis, DNA; D013601:T-Lymphocytes / Q000276:immunology*; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology*
chemical_list: D006680:HLA Antigens; D016056:Immunodominant Epitopes; D054301:gag Gene Products, Human Immunodeficiency Virus; D007371:Interferon-gamma