title: An algorithm for evaluating human cytotoxic T lymphocyte responses to candidate AIDS vaccines.
abstract: Development of an effective vaccine against HIV-1 will likely require the induction of a broad array of immune responses, including virus-specific CTLs and neutralizing antibodies. One promising vaccine approach involves live recombinant canarypox (CP)-based vectors (ALVAC) containing multiple HIV-1 genes. In phase I clinical trials in HIV-1-seronegative volunteers, the cumulative rate of detection of HIV-1-specific CTLs has been as high as 60-70%. In the present study, the factors associated with CTL responsiveness were evaluated in a subset of vaccinees immunized with a CP vector expressing portions of the gag, pro, and env genes of HIV-1 (ALVAC-HIV). CTL responses were detected in one of seven examined. While the responding individual had both CD4+ and CD8+ CTLs directed at multiple HIV-1 antigens, this response was not detectable 1 year after the last vaccination. In-depth characterization of "CTL nonresponders" showed that nonresponsiveness was not associated with defects in antigen processing or presentation. A generalized defect in CTL responsiveness was ruled out by parallel assays to detect CMV-specific CTLs from these same volunteers. Furthermore, HIV-1-specific memory CTLs were not detectable by peptide stimulation or by a novel technique for flow cytometric visualization of Gag epitope-specific T lymphocytes while HIV-1-seropositive donors frequently had 0.1-3% of CD8+ cells stain positively for this epitope (SLYNTVATL). Taken together, these results suggest that the lack of detectable HIV-1 CTLs in these volunteers was not due to classic MHC-linked nonresponsiveness.
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. lcarruth@welchlink.welch.jhu.edu
authors.forename: L M
authors.initials: LM
authors.lastname: Carruth
authors.forename: T F
authors.initials: TF
authors.lastname: Greten
authors.forename: C E
authors.initials: CE
authors.lastname: Murray
authors.forename: M G
authors.initials: MG
authors.lastname: Castro
authors.forename: S N
authors.initials: SN
authors.lastname: Crone
authors.forename: W
authors.initials: W
authors.lastname: Pavlat
authors.forename: J P
authors.initials: JP
authors.lastname: Schneck
authors.forename: R F
authors.initials: RF
authors.lastname: Siliciano
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology*; D000465:Algorithms; D000818:Animals; D017951:Antigen Presentation; D018150:Avipoxvirus; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D004279:DNA, Viral / Q000008:administration & dosage; D005434:Flow Cytometry; D015488:HIV Antigens / Q000276:immunology; D015699:HIV Envelope Protein gp120 / Q000235:genetics; D018023:HIV Seronegativity; D015497:HIV-1 / Q000276:immunology; D006801:Humans; D051379:Mice; D018448:Models, Immunological; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D016915:AIDS Vaccines; D004279:DNA, Viral; D015488:HIV Antigens; D015699:HIV Envelope Protein gp120