INDUCTION OF A EFFECTOR MEMORY CD4+ T CELL RESPONSE BY ATTENUATED SIV

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。病毒特异性CD4+ T淋巴细胞可能在启动和维持抗病毒免疫中发挥核心作用。在感染SIV毒株的猕猴中对这些反应进行调查，为更好地了解这些反应与疾病进展和保护性免疫之间的关系提供了极好的机会。我们研究了慢性感染减毒或致病性SIV毒株的恒河猴的SIV特异性CD4+ T细胞反应。对sivdeltanef感染动物的分析显示，SIV特异性CD4+T反应的频率相对较高，占所有针对多种SIV蛋白的CD4+T淋巴细胞的4% - 10%。在野生型siv感染动物中检测到gag特异性CD4+T细胞反应的频率比sivdeltanef疫苗接种动物低5至10倍，并且与血浆病毒血症水平呈负相关。表型分析显示，来自deltanef感染动物的siv特异性CD4+细胞主要是CD28- CCR7-和CCR5-，与中间分化阶段一致，但也包括完全分化的CD45RA+CCR7-亚群。相比之下，siv感染动物的siv特异性CD4+ T细胞主要是CD28+ CCR7+和CCR5+，与早期到中期分化阶段一致。deltanefe感染动物的CD45RA+CCR7-CD4+亚群对效应CD4+T细胞高度富集，在Gag肽刺激后穿孔素的表达和溶酶体膜蛋白CD107a的上调证明了这一点。SIVdeltanef诱导具有直接效应功能的高频病毒特异性CD4+T细胞应答的能力可能在接种减毒SIV毒株产生的保护性免疫中发挥关键作用。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Virus-specific CD4+ T lymphocytes are likely to play a central role in initiating and maintaining antiviral immunity. Investigation of these responses in macaques infected with SIV strains offers an excellent opportunity to better understand the relationship of these responses to disease progression and protective immunity. We investigated SIV-specific CD4+ T cell responses in rhesus macaques chronically infected with attenuated or pathogenic SIV strains. Analysis of SIVdeltanef-infected animals revealed a relatively high frequency SIV-specific CD4+T response representing 4 percent-10 percent of all CD4+ T lymphocytes that was directed against multiple SIV proteins. Gag-specific CD4+T cell responses in wild-type SIV-infected animals were detected at a 5 to 10-fold lower frequency than in SIVdeltanef-vaccinated animals and were inversely correlated with the level of plasma viremia. Phenotypic analysis revealed that SIV-specific CD4+ cells from deltanef-infected animals were predominantly CD28- CCR7- and CCR5-, consistent with an intermediate differentiation stage, but also included a fully differentiated CD45RA+CCR7- subset. In contrast, SIV-specific CD4+ T cells from SIV-infected animals were mostly CD28+ CCR7+ and CCR5+, consistent with an early to intermediate differentiation stage. The CD45RA+CCR7-CD4+ subset from deltanef-infected animals was highly enriched for effector CD4+T cells, as evidenced by expression of perforin and upregulation of the lysosomal membrane protein CD107a following stimulation with Gag peptides. The ability of SIVdeltanef to induce a high-frequency virus-specific CD4+T cell response with direct effector function may play a key role in protective immunity produced by vaccination with attenuated SIV strains.