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研究発表を行った学会；
・Keystone Symposia (HIV Vaccine and Viral Immunity)
　２０１０年　３月２１日〜２６日（Banff, Alberta, Canada）

タイトル；The cross-reactive capacity of HIV-specific CTLs towards HIV variant antigens is dependent on their cognate peptides.
　
発表者；　本園　千尋　氏
　　　（熊本大学　エイズ学研究センター　上野プロジェクト研究室）

Abstract；
It is becoming evident that there is a difference in specificities and the antiviral effectiveness of CTLs between early and chronic phases of HIV infection. But the cross-reactive capacity of these CTL responses remains elusive although the promiscuous recognition of HIV variant antigens by CTLs is thought to be important for efficient virus containment in vivo. Here, we analyzed the cross-reactive nature of immunodominant HLA-B35+ restricted CTLs specific for closely related two Nef epitopes: a short epitope (Nef78-85: VPLRPMTY, VY8) dominant in early phase of HIV infection, which subsequently shift to an N-terminally extended epitope (Nef75-85: RPQVPLRPMTY, RY11) in the chronic phase. T-cell-receptor (TCR) clonotype analysis of CTLs specific for VY8 and RY11 isolated from six HLA-B35+ HIV-infected individuals revealed that the TCR-a variable segments were all identical among CTL clones specific for VY8 but varied among those specific for RY11.The TCR-b usage of the CTL clones was highly variable. To precisely define the cross-reactive nature of individual TCRs, we functionally reconstructed six TCRs specific for VY8 and RY11 on TCR-deficient T cells. A naturally-arising variant antigen (Tyr to Phe at the C-terminus) which is associated with HLA-B35 at early infection appeared to be recognized by all RY11-specific TCRs but by none of VY8-specific TCRs. These data suggest the different promiscuous profiles between the two groups of CTLs. We then sought to define the fine mapping of cross-reactive antigens recognized by these TCRs using a peptide library containing an amino acid substitution at every position in the wild-type peptide. The cross-reactive variant antigens recognized by TCRs showed highly overlapping within the VY8-specific group but substantially different between the two groups. Moreover, VY8 and RY11-specific TCRs recognized 18.3±3.1 out of 144 (~13 %) and 50.5±12.4 out of 198 (~26 %) variant peptides, respectively, suggesting that VY8-specific TCRs could recognize significantly less numbers of variant antigens than RY11-specific TCRs. Our results indicate that the VY8 peptide, an immunodominant epitope at early infection, mounts CTL responses with a limited TCR diversity and promiscuity. The findings that the cross-reactive capacity of CTL responses is highly dependent on the cognate epitope peptides provide better insights for a rational vaccine design for HIV infection.