IMMUNE ESCAPE EVOL IN IMMUNODOMINANT CTL EPITODE IN SIVMAC239 INFECTED MANGABEY

黑白眉猴是非洲旧大陆的灵长类动物， 感染SIV，血浆SIV水平高，但不进展 为了了解这种受保护状态的免疫基础， 研究了SIV特异性CTL活性， SIV感染和随后用SIVmac 239实验感染 对12例自然感染的小鼠进行了SIV特异性CTL活性分析 在7个受试者的新鲜PBMC中未检测到白眉猴SIV特异性CTL， 7只动物，即使在高效应物与靶标比率下测试， 提示循环中缺乏活化的SIV特异性CTL 在离体抗原特异性刺激后， 可检测到SIV特异性的异质性强CTL活性， 仅4/12只动物仍然无法检测到或不一致地存在 在5/12只动物中可检出，在3/12只动物中可检出较低水平 在病毒载量的大小和 SIV特异性CTL活性的强度SIV特异性CTL克隆是 分离自SIVmac 239和自然感染的白眉猴克隆 其对gag、env和nef蛋白的活性被高度定位于 SIV基因组的保守区env特异性表位定位于 高度保守的9-mer肽，YVPCHIRQI，位于V4之外 gag表位定位于12-mer肽， 在p27（aa 281-292）中，这些表位是免疫显性的，如大量CTL 裂解的靶点呈递表位的程度与 表达整个蛋白质的靶标单个nef特异性CTL克隆 从自然感染的白眉猴中分离出20聚体， 氨基酸21-40的表位图对这些动物的后续研究可能会揭示 病毒与CTL相互作用产生非致病性SIV 感染

Sooty mangabeys are African Old World primates that are naturally infected with SIV, have high plasma SIV levels and yet do not progress to AIDS To understand the immune basis of this protected state, SIV-specific CTL activity was studied in sooty mangabeys with natural SIV infection and following experimental infection with SIVmac239 SIV-specific CTL activity was analysed in 12 naturally infected sooty mangabeys SIV-specific CTL were not detectable in fresh PBMC from 7 of 7 animals, even when tested at high effector to target ratios, suggesting the absence of circulating activated SIV-specific CTL Following ex vivo antigen-specific stimulation, the response was heterogeneous Vigorous SIV-specific CTL activity was detectable in only 4/12 animals It remained undetectable or inconsistently present in 5/12 animals and detectable at low levels in 3/12 animals No correlation was observed between the magnitude of viral load and the strength of SIV-specific CTL activity SIV-specific CTL clones were isolated from SIVmac239 and naturally infected sooty mangabeys Clones with activity against gag, env and nef proteins mapped to highly conserved regions of the SIV genome An env-specific epitope maps to a highly conserved 9-mer peptide, YVPCHIRQI, located just beyond the V4 region of gp120, while a gag epitope was localized to a 12-mer peptide in p27 (aa 281-292) These epitopes are immunodominant, as bulk CTL lysed targets presenting the epitope to an extent comparable to targets expressing the entire protein A single nef-specific CTL clone was isolated from a naturally infected sooty mangabey and the 20-mer epitope maps to aa 21-40 Follow up of these animals may shed light on the interactions between virus and CTL that result in apathogenic SIV infection