title: Abrogation of AIDS vaccine-induced cytotoxic T-lymphocyte efficacy in vivo due to a change in viral epitope flanking sequences.
abstract: A current promising AIDS vaccine strategy is to elicit CD8(+) cytotoxic T lymphocyte (CTL) responses that broadly recognize highly-diversified HIVs. In our previous vaccine trial eliciting simian immunodeficiency virus (SIV) mac239 Gag-specific CTL responses, a group of Burmese rhesus macaques possessing a major histocompatibility complex haplotype 90-120-Ia have shown vaccine-based viral control against a homologous SIVmac239 challenge. Vaccine-induced Gag(206-216) epitope-specific CTL responses exerted strong selective pressure on the virus in this control. Here, we have evaluated in vivo efficacy of vaccine-induced Gag(206-216)-specific CTL responses in two 90-120-Ia-positive macaques against challenge with a heterologous SIVsmE543-3 that has the same Gag(206-216) epitope sequence with SIVmac239. Despite efficient Gag(206-216)-specific CTL induction by vaccination, both vaccinees failed to control SIVsmE543-3 replication and neither of them showed mutations within the Gag(206-216) epitope. Further analysis indicated that Gag(206-216)-specific CTLs failed to show responses against SIVsmE543-3 infection due to a change from aspartate to glutamate at Gag residue 205 immediately preceding the amino terminus of Gag(206-216) epitope. Our results suggest that even vaccine-induced CTL efficacy can be abrogated by a single amino acid change in viral epitope flanking region, underlining the influence of viral epitope flanking sequences on CTL-based AIDS vaccine efficacy.
authors.affiliation: International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Chikaya
authors.initials: C
authors.lastname: Moriya
authors.forename: Hiroko
authors.initials: H
authors.lastname: Igarashi
authors.forename: Akiko
authors.initials: A
authors.lastname: Takeda
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Tsukamoto
authors.forename: Miki
authors.initials: M
authors.lastname: Kawada
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Makoto
authors.initials: M
authors.lastname: Inoue
authors.forename: Akihiro
authors.initials: A
authors.lastname: Iida
authors.forename: Tsugumine
authors.initials: T
authors.lastname: Shu
authors.forename: Mamoru
authors.initials: M
authors.lastname: Hasegawa
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Nagai
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Matano
mesh_terms: D000281:Administration, Intranasal; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D002478:Cells, Cultured; D018984:Epitopes, T-Lymphocyte / Q000235:genetics*; D015683:Gene Products, gag / Q000276:immunology; D007117:Immunization, Secondary; D007273:Injections, Intramuscular; D007963:Leukocytes, Mononuclear; D008253:Macaca mulatta; D008969:Molecular Sequence Data; D018449:SAIDS Vaccines / Q000008:administration & dosage / Q000276:immunology*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000517:prevention & control*; D015302:Simian Immunodeficiency Virus / Q000502:physiology*; D013045:Species Specificity; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014611:Vaccination; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000276:immunology; D014779:Virus Replication
chemical_list: D018984:Epitopes, T-Lymphocyte; D015683:Gene Products, gag; D018449:SAIDS Vaccines; D019444:Vaccines, DNA