title: Identification of Immunogenic Cytotoxic T Lymphocyte Epitopes Containing Drug Resistance Mutations in Antiretroviral Treatment-Naïve HIV-Infected Individuals.
abstract: BACKGROUND
  Therapeutic HIV vaccines may prove helpful to intensify antiretroviral treatment (ART) efficacy and may be an integral part of future cure strategies.
  
  
  METHODS
  We examined IFN-gamma ELISpot responses to a panel of 218 HIV clade B consensus-based HIV protease-reverse transcriptase peptides, designed to mimic previously described and predicted cytotoxic T lymphocyte epitopes overlapping drug resistance (DR) positions, that either included the consensus sequence or the DR variant sequence, in 49 ART-naïve HIV-infected individuals. Next generation sequencing was used to assess the presence of minority DR variants in circulating viral populations.
  
  
  RESULTS
  Although a wide spectrum of differential magnitudes of response to DR vs. WT peptide pairs was observed, responses to DR peptides were frequent and strong in the study cohort. No difference between the median magnitudes of response to DR vs. WT peptides was observed. Interestingly, of the 22 peptides that were recognized by >15% of the participants, two-thirds (64%) corresponded to DR peptides. When analysing responses per peptide pair per individual, responses to only WT (median 4 pairs/individual) or DR (median 6 pairs/individual) were more common than responses to both WT and DR (median 2 pairs/individual; p<0.001). While the presence of ELISpot responses to WT peptides was frequently associated with the presence of the corresponding peptide sequence in the patient's virus (mean 68% of cases), responses to DR peptides were generally not associated with the presence of DR mutations in the viral population, even at low frequencies (mean 1.4% of cases; p = 0.0002).
  
  
  CONCLUSIONS
  Our data suggests that DR peptides are frequently immunogenic and raises the potential benefit of broadening the antigens included in a therapeutic vaccine approach to immunogenic epitopes containing common DR sequences. Further studies are needed to assess the quality of responses elicited by DR peptides.
authors.affiliation: Centre for Infectious Diseases Research, National Institute of Respiratory Diseases, Mexico City, Mexico.
authors.forename: Juan
authors.initials: J
authors.lastname: Blanco-Heredia
authors.affiliation: Centre for Infectious Diseases Research, National Institute of Respiratory Diseases, Mexico City, Mexico.|Max Planck Institute for Molecular Biomedicine, Münster, Germany.
authors.forename: Aarón
authors.initials: A
authors.lastname: Lecanda
authors.affiliation: Centre for Infectious Diseases Research, National Institute of Respiratory Diseases, Mexico City, Mexico.
authors.forename: Humberto
authors.initials: H
authors.lastname: Valenzuela-Ponce
authors.affiliation: IrsiCaixa AIDS Research Institute-HIVACAT, Hospital Germans Trias i Pujol, Badalona, Spain.|Institució Catalana de Recerca i Estudis Avançats (ICREA)-UAB, Barcelona, Spain.|University of Vic and Central Catalonia, Vic, Spain.
authors.forename: Christian
authors.initials: C
authors.lastname: Brander
authors.affiliation: Centre for Infectious Diseases Research, National Institute of Respiratory Diseases, Mexico City, Mexico.
authors.forename: Santiago
authors.initials: S
authors.lastname: Ávila-Ríos
authors.affiliation: Centre for Infectious Diseases Research, National Institute of Respiratory Diseases, Mexico City, Mexico.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Reyes-Terán
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology; D044966:Anti-Retroviral Agents / Q000627:therapeutic use; D004351:Drug Resistance / Q000235:genetics*; D058501:Enzyme-Linked Immunospot Assay; D018984:Epitopes, T-Lymphocyte / Q000235:genetics*; D015658:HIV Infections / Q000235:genetics* / Q000276:immunology*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D009154:Mutation; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D016915:AIDS Vaccines; D044966:Anti-Retroviral Agents; D018984:Epitopes, T-Lymphocyte