Price David A, Asher Tedi E, Wilson Nancy A, Nason Martha C, Brenchley Jason M, Metzler Ian S, Venturi Vanessa, Gostick Emma, Chattopadhyay Pratip K, Roederer Mario, Davenport Miles P, Watkins David I, Douek Daniel C
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
J Exp Med. 2009 Apr 13;206(4):923-36. doi: 10.1084/jem.20081127. Epub 2009 Apr 6.
Despite the pressing need for an AIDS vaccine, the determinants of protective immunity to HIV remain concealed within the complexity of adaptive immune responses. We dissected immunodominant virus-specific CD8(+) T cell populations in Mamu-A*01(+) rhesus macaques with primary SIV infection to elucidate the hallmarks of effective immunity at the level of individual constituent clonotypes, which were identified according to the expression of distinct T cell receptors (TCRs). The number of public clonotypes, defined as those that expressed identical TCR beta-chain amino acid sequences and recurred in multiple individuals, contained within the acute phase CD8(+) T cell population specific for the biologically constrained Gag CM9 (CTPYDINQM; residues 181-189) epitope correlated negatively with the virus load set point. This independent molecular signature of protection was confirmed in a prospective vaccine trial, in which clonotype engagement was governed by the nature of the antigen rather than the context of exposure and public clonotype usage was associated with enhanced recognition of epitope variants. Thus, the pattern of antigen-specific clonotype recruitment within a protective CD8(+) T cell population is a prognostic indicator of vaccine efficacy and biological outcome in an AIDS virus infection.
尽管对艾滋病疫苗有着迫切需求，但针对HIV的保护性免疫的决定因素仍隐藏在适应性免疫反应的复杂性之中。我们剖析了初次感染SIV的Mamu-A*01(+)恒河猴体内免疫显性的病毒特异性CD8(+) T细胞群体，以阐明在个体组成克隆型水平上有效免疫的特征，这些克隆型是根据不同T细胞受体（TCR）的表达来确定的。公共克隆型的数量，定义为那些表达相同TCRβ链氨基酸序列且在多个个体中反复出现的克隆型，在针对生物学上受限的Gag CM9（CTPYDINQM；第181 - 189位氨基酸残基）表位的急性期CD8(+) T细胞群体中，与病毒载量设定点呈负相关。这种保护的独立分子特征在前瞻性疫苗试验中得到了证实，在该试验中，克隆型的参与由抗原的性质而非暴露背景决定，并且公共克隆型的使用与表位变体的增强识别相关。因此，保护性CD8(+) T细胞群体内抗原特异性克隆型募集的模式是艾滋病病毒感染中疫苗疗效和生物学结果的一个预后指标。
