title: Mapping HIV-1 vaccine induced T-cell responses: bias towards less-conserved regions and potential impact on vaccine efficacy in the Step study.
abstract: T cell directed HIV vaccines are based upon the induction of CD8+ T cell memory responses that would be effective in inhibiting infection and subsequent replication of an infecting HIV-1 strain, a process that requires a match or near-match between the epitope induced by vaccination and the infecting viral strain. We compared the frequency and specificity of the CTL epitope responses elicited by the replication-defective Ad5 gag/pol/nef vaccine used in the Step trial with the likelihood of encountering those epitopes among recently sequenced Clade B isolates of HIV-1. Among vaccinees with detectable 15-mer peptide pool ELISpot responses, there was a median of four (one Gag, one Nef and two Pol) CD8 epitopes per vaccinee detected by 9-mer peptide ELISpot assay. Importantly, frequency analysis of the mapped epitopes indicated that there was a significant skewing of the T cell response; variable epitopes were detected more frequently than would be expected from an unbiased sampling of the vaccine sequences. Correspondingly, the most highly conserved epitopes in Gag, Pol, and Nef (defined by presence in >80% of sequences currently in the Los Alamos database www.hiv.lanl.gov) were detected at a lower frequency than unbiased sampling, similar to the frequency reported for responses to natural infection, suggesting potential epitope masking of these responses. This may be a generic mechanism used by the virus in both contexts to escape effective T cell immune surveillance. The disappointing results of the Step trial raise the bar for future HIV vaccine candidates. This report highlights the bias towards less-conserved epitopes present in the same vaccine used in the Step trial. Development of vaccine strategies that can elicit a greater breadth of responses, and towards conserved regions of the genome in particular, are critical requirements for effective T-cell based vaccines against HIV-1.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00849680, A Study of Safety, Tolerability, and Immunogenicity of the MRKAd5 Gag/Pol/Nef Vaccine in Healthy Adults.
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Fusheng
authors.initials: F
authors.lastname: Li
authors.forename: Adam C
authors.initials: AC
authors.lastname: Finnefrock
authors.forename: Sheri A
authors.initials: SA
authors.lastname: Dubey
authors.forename: Bette T M
authors.initials: BT
authors.lastname: Korber
authors.forename: James
authors.initials: J
authors.lastname: Szinger
authors.forename: Suzanne
authors.initials: S
authors.lastname: Cole
authors.forename: M Juliana
authors.initials: MJ
authors.lastname: McElrath
authors.forename: John W
authors.initials: JW
authors.lastname: Shiver
authors.forename: Danilo R
authors.initials: DR
authors.lastname: Casimiro
authors.forename: Lawrence
authors.initials: L
authors.lastname: Corey
authors.forename: Steven G
authors.initials: SG
authors.lastname: Self
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology*; D000328:Adult; D000595:Amino Acid Sequence; D015982:Bias; D017321:Clinical Trials, Phase I as Topic; D017124:Conserved Sequence / Q000276:immunology*; D018604:Epitope Mapping; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000276:immunology; D005260:Female; D015658:HIV Infections / Q000276:immunology / Q000628:therapy; D015497:HIV-1 / Q000276:immunology*; D054298:Human Immunodeficiency Virus Proteins / Q000737:chemistry / Q000276:immunology; D006801:Humans; D008297:Male; D013601:T-Lymphocytes / Q000276:immunology*; D016896:Treatment Outcome
chemical_list: D016915:AIDS Vaccines; D018984:Epitopes, T-Lymphocyte; D054298:Human Immunodeficiency Virus Proteins