A DECLINE IN CC-CHEMOKINE GENE EXPRESSION DURING PRIMARY SHIV INFECTION

原发性 SHIV 感染期间 CC 趋化因子基因表达下降

• 批准号: 7716260
• 负责人: KAROL SESTAK
• 金额: $ 6.46万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-21 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7716260
• 关键词: Acute; Animals; CCL3 gene; CCL4 gene; CCL5 gene; CD4 Positive T Lymphocytes; Cells; Chronic; Computer Retrieval of Information on Scientific Projects Database; Confocal Microscopy; Down-Regulation; Evaluation; Flow Cytometry; Funding; Future; Gene Expression; Grant; Gut associated lymphoid tissue; HIV; HIV vaccine; HIV-1; Immunomodulators; In Vitro; Infection; Institution; Macaca; Macaca mulatta; Measures; Messenger RNA; Modeling; Oligonucleotides; Polymerase Chain Reaction; Primates; RANTES; Research; Research Personnel; Resources; Role; Sampling; Source; Staging; T-Cell Depletion; Testing; Time; United States National Institutes of Health; Viral; Viral Load result; Virus Diseases; beta-Chemokines; day; in vivo; peripheral blood; response; simian human immunodeficiency virus

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. The CC-chemokines CCL3, CCL4 and CCL5 have been found to block the entry of CCR5-tropic HIV into host cells and to suppress the viral replication in vitro, but the in vivo role of endogenous CC-chemokines in HIV-1 infection is still incompletely understood. In this study, the primate host CCL3, CCL4 and CCL5 gene expression was evaluated in response to simian-human immunodeficiency virus (SHIV) infection in rhesus macaque model. Five rhesus macaques were inoculated with CCR5-tropic SHIVSF162P4. The mRNA levels of CCL3, CCL4 and CCL5 were measured by real-time PCR at post inoculation day (PID) 0, 7, 14, 21, 35, 56 and 180 in peripheral blood. In addition, a selected subset of samples from CXCR4-tropic SHIVKu1-infected macaques was included with objective to compare the differences in CC-chemokine down-regulation caused by the two SHIVs. Gut-associated lymphoid tissues (GALT) collected from SHIVSF162P4-infected animals were also tested by flow cytometry and confocal microscopy to corroborate the gene expression results. Predictably, higher viral loads and CD4+ T cell losses were observed at PID 14 in macaques infected with SHIVKu1 than with SHIVSF162P4. A decline in CC-chemokine gene expression was also found during primary (PID 7-21), but not chronic (PID 180) stage of infection. It was determined that A) SHIVSF162P4 down-regulated the CC-chemokine gene expression during acute stage of infection to a greater extent (p0.05) than SHIVKu1, and B) such down-regulation was not paralleled with the CD4+ T cell depletion. Evaluation of CC-chemokine enhancing immunomodulators such as synthetic CpG-oligonucleotides could be explored in future HIV vaccine studies.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 CC趋化因子CCL3、CCL4和CCL5已被发现可阻止CCR5趋化性HIV进入宿主细胞并在体外抑制病毒复制，但内源性CC趋化因子在HIV-1感染中的体内作用仍不完全清楚。在这项研究中，在恒河猴模型中评估了灵长类宿主 CCL3、CCL4 和 CCL5 基因表达对猿猴人类免疫缺陷病毒 (SHIV) 感染的反应。五只恒河猴接种了 CCR5 趋向性 SHIVSF162P4。在接种后第0、7、14、21、35、56和180天通过实时PCR测量外周血中CCL3、CCL4和CCL5的mRNA水平。此外，还包括来自 CXCR4 嗜性 SHIVKu1 感染的猕猴的选定子集样本，目的是比较两种 SHIV 引起的 CC 趋化因子下调的差异。还通过流式细胞术和共聚焦显微镜对从 SHIVSF162P4 感染的动物收集的肠道相关淋巴组织 (GALT) 进行了测试，以证实基因表达结果。可以预见的是，在 PID 14 时，感染 SHIVKu1 的猕猴比感染 SHIVSF162P4 的猕猴观察到更高的病毒载量和 CD4+ T 细胞损失。在感染的初级阶段（PID 7-21）也发现了 CC 趋化因子基因表达的下降，但在感染的慢性阶段（PID 180）则没有。确定 A) SHIVSF162P4 在感染急性期下调 CC 趋化因子基因表达的程度比 SHIVKu1 更大 (p0.05)，并且 B) 这种下调与 CD4+ T 细胞耗竭不平行。在未来的 HIV 疫苗研究中可以探索对 CC 趋化因子增强免疫调节剂（例如合成 CpG 寡核苷酸）的评估。