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

减毒 SIV 诱导效应记忆 CD4 T 细胞反应

• 批准号: 7562056
• 负责人: M-C GAUDUIN
• 金额: $ 5.2万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7562056
• 关键词: Animals; Antiviral Agents; Attenuated; CCR5 gene; CD28 gene; CD4 Positive T Lymphocytes; Cells; Computer Retrieval of Information on Scientific Projects Database; Disease Progression; Frequencies; Funding; Gagging; Grant; Immunity; Institution; Investigation; Macaca; Macaca mulatta; Membrane Proteins; Memory; Peptides; Plasma; Play; Proteins; Research; Research Personnel; Resources; Role; SIV; Source; Staging; United States National Institutes of Health; Up-Regulation; Vaccinated; Vaccination; Viremia; Virus; perforin; response

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 nef-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.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 病毒特异性的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。对感染SIV毒株的猕猴进行这些反应的研究，为更好地了解这些反应与疾病进展和保护性免疫的关系提供了一个极好的机会。我们研究了SIV减毒株或致病株慢性感染恒河猴的SIV特异性CD4+T细胞反应。对感染SIVdeltanef的动物的分析显示，SIV特异性的CD4+T反应频率相对较高，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感染的动物中，检测到GAG特异性的CD4+T细胞反应的频率比接种SIVdeltanef的动物低5-10倍，并且与血浆病毒血症水平呈负相关。表型分析显示，新城疫感染动物体内的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，来自SIV感染动物的SIV特异性CD4+T细胞主要是CD28+CCR7+和CCR5+，这与早期到中期的分化阶段一致。Deltanef感染动物的CD45RA+CCR7-CD4+亚群高度富含效应的CD4+T细胞，穿孔素的表达和GAG多肽刺激后溶酶体膜蛋白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SIV减毒株免疫产生的保护性免疫中起关键作用。