RESUMO
Only limited cytotoxic T lymphocyte (CTL) epitope mapping has been done in nonsubtype B HIV-infected persons. We used molecular immunogenetic tools to determine HIV-specific CTL responses in HIV-1 Env subtype E-infected female sex workers (FSWs) from northern Thailand, where more than 50% of the population is HLA-A11 positive. EpiMatrix, a computer-based T cell epitope prediction algorithm, and a manual editing approach were used to predict 77 possible HLA-A11 CTL epitopes in HIV-1, some of which were conserved between subtypes B and E. MHC binding of these peptides was determined in an HLA-A11 stabilization assay, and binding peptides were tested for CTL recognition in eight HLA-A11-positive FSWs. Subtype E versions of known HLA-A2 subtype B HIV epitopes were also tested in four HLA-A2 positive FSWs. CTL responses were detected in all HLA-A11-positive and in three of four HLA-A2-positive persons. Among the 12 FSWs responses to peptides were found to Pol in 9 (75%), Env in 7 (58%), Nef in 5 (42%), and Gag in 5 (42%), and to conserved epitopes in 8 (67%). To identify HLA-A11 CTL epitopes in the absence of prediction tools, it would have been necessary to test almost 3000 10-mer peptides. EpiMatrix and manual predictions reduced this number to 77, of which 26 were MHC binding and 12 were CTL epitopes. Six of these HLA-A11 CTL epitopes have not been previously reported and are located in RT, gp120, and gp41. This report of CTL responses in subtype E-infected individuals defines epitopes that may be useful in HIV pathogenesis or vaccine studies.
Assuntos
Epitopos de Linfócito T/análise , Infecções por HIV/imunologia , HIV-1/imunologia , Antígenos HLA-A/imunologia , Linfócitos T Citotóxicos/imunologia , Algoritmos , Estudos de Coortes , Testes Imunológicos de Citotoxicidade , Mapeamento de Epitopos , Epitopos de Linfócito T/imunologia , Feminino , Produtos do Gene env/imunologia , Produtos do Gene gag/imunologia , Produtos do Gene nef/imunologia , Produtos do Gene pol/imunologia , Infecções por HIV/virologia , HIV-1/genética , Antígeno HLA-A11 , Antígeno HLA-A2/imunologia , Humanos , Epitopos Imunodominantes/análise , Epitopos Imunodominantes/imunologia , Fragmentos de Peptídeos/síntese química , Fragmentos de Peptídeos/imunologia , Trabalho Sexual , Tailândia , Proteínas Virais/síntese química , Proteínas Virais/imunologia , Produtos do Gene nef do Vírus da Imunodeficiência HumanaRESUMO
Improvements in HIV-1 vaccines are urgently needed since many of the available vaccines are weak immunogens. We examined the ability of CRL1005, a novel nonionic block copolymer adjuvant, to improve the immunogenicity of multiple HIV-1 envelope vaccines: six gp120s and single and multiple V3 peptides (MAPs). Formulation of vaccine with adjuvant, as compared with alum or saline, enhanced antibody titer in mice up to 200-fold, with antibody half-lives of >200 days. For most vaccinations, an oil-in-water formulation induced the highest antibody titers; for some antigens, however, particularly single peptides, water-in-oil (w/o) was better. Antigen cross-reactivity was optimized by formulation in w/o, while addition of detoxified lipopolysaccharide enhanced levels of IgG2a and IgG2b. After more than 1 year of observation, no vaccine-related toxicity was observed and emulsified antigen in encapsulated depots was found at immunization sites of w/o-immunized animals. No other adjuvant has been reported to induce such long-lasting antibodies, and the ability of CRL1005 to greatly amplify and qualitatively modify antibody responses suggests that it may be useful in developing improved HIV vaccines for humans.