Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
PLoS One. 2011;6(8):e23515. doi: 10.1371/journal.pone.0023515. Epub 2011 Aug 26.
Several lines of evidence suggest that HIV/SIV-specific CD8(+) T cells play a critical role in the control of viral replication. Recently we observed high levels of viremia in Indian rhesus macaques vaccinated with a segment of SIVmac239 Gag (Gag(45-269)) that were subsequently infected with SIVsmE660. These seven Mamu-A*01(+) animals developed CD8(+) T cell responses against an immunodominant epitope in Gag, GagCM9, yet failed to control virus replication. We carried out a series of immunological and virological assays to understand why these Gag-specific CD8(+) T cells could not control virus replication in vivo. GagCM9-specific CD8(+) T cells from all of the animals were multifunctional and were found in the colonic mucosa. Additionally, GagCM9-specific CD8(+) T cells accessed B cell follicles, the primary residence of SIV-infected cells in lymph nodes, with effector to target ratios between 20-250 GagCM9-specific CD8(+) T cells per SIV-producing cell. Interestingly, vaccinated animals had few public TCR clonotypes within the GagCM9-specific CD8(+) T cell population pre- and post-infection. The number of public TCR clonotypes expressed by GagCM9-specific CD8(+) T cells post-infection significantly inversely correlated with chronic phase viral load. It is possible that these seven animals failed to control viral replication because of the narrow TCR repertoire expressed by the GagCM9-specific CD8(+) T cell population elicited by vaccination and infection.
有几条证据表明，HIV/SIV 特异性 CD8(+) T 细胞在控制病毒复制方面发挥着关键作用。最近，我们观察到，用 SIVmac239 Gag（Gag(45-269)）的一个片段接种的印度恒河猴体内病毒载量很高，随后这些猕猴又感染了 SIVsmE660。这 7 只 Mamu-A*01(+)动物针对 Gag 中的一个免疫优势表位 GagCM9 产生了 CD8(+) T 细胞反应，但未能控制病毒复制。我们进行了一系列免疫学和病毒学检测，以了解为什么这些 Gag 特异性 CD8(+) T 细胞不能在体内控制病毒复制。从所有动物中分离出的 GagCM9 特异性 CD8(+) T 细胞具有多功能性，存在于结肠黏膜中。此外，GagCM9 特异性 CD8(+) T 细胞进入了 B 细胞滤泡，这是淋巴结中 SIV 感染细胞的主要栖息地，效应物与靶细胞的比例在 20-250 之间。有趣的是，接种疫苗的动物在感染前后的 GagCM9 特异性 CD8(+) T 细胞群体中，公共 TCR 克隆型数量很少。感染后，GagCM9 特异性 CD8(+) T 细胞表达的公共 TCR 克隆型数量与慢性期病毒载量呈显著负相关。这 7 只动物可能由于疫苗接种和感染引发的 GagCM9 特异性 CD8(+) T 细胞群体表达的 TCR repertoire 狭窄，未能控制病毒复制。
