GagCM9-Specific CD8+ T Cells Expressing Limited Public TCR Clonotypes Do Not Suppress SIV Replication In Vivo

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 (Gag45–269) 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.

多项研究证据表明，人类免疫缺陷病毒（HIV）/猴免疫缺陷病毒（SIV）特异性CD8+ T细胞（CD8+ T cells）在病毒复制的调控中发挥关键作用。近期我们发现，接种了SIVmac239 Gag片段（Gag45–269）的印度恒河猴，在随后感染SIVsmE660毒株后出现了高水平病毒血症（viremia）。这7只Mamu-A*01阳性的恒河猴，针对Gag蛋白中的免疫显性表位（immunodominant epitope）GagCM9产生了CD8+ T细胞应答，但未能有效控制病毒复制。我们开展了一系列免疫学与病毒学检测，以探究为何这些Gag特异性CD8+ T细胞无法在体内（in vivo）调控病毒复制。所有受试恒河猴体内的GagCM9特异性CD8+ T细胞均具备多功能性，且可在结肠黏膜（colonic mucosa）中被检测到。此外，GagCM9特异性CD8+ T细胞可迁移至B细胞滤泡（B cell follicles）——这是淋巴结内SIV感染细胞的主要定植部位，其效应细胞与靶细胞比例为每1个产毒SIV细胞对应20~250个GagCM9特异性CD8+ T细胞。值得注意的是，无论感染前后，接种组恒河猴的GagCM9特异性CD8+ T细胞群体中，公共TCR克隆型（public TCR clonotypes）的数量均极少。感染后，GagCM9特异性CD8+ T细胞所表达的公共TCR克隆型数量，与慢性期病毒载量（chronic phase viral load）呈显著负相关。这7只恒河猴未能控制病毒复制，可能是因为疫苗接种与感染所诱导的GagCM9特异性CD8+ T细胞群体所表达的T细胞受体库（TCR repertoire）较为狭窄。