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

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。 CC趋化因子CCL3、CCL4和CCL5在体外可阻断嗜CCR5的HIV进入宿主细胞并抑制病毒复制，但内源性CC趋化因子在体内对HIV-1感染的作用尚不完全清楚。本研究在恒河猴模型中研究了灵长类宿主CCL3、CCL4和CCL5基因在猴-人免疫缺陷病毒(SHIV)感染后的表达。5只恒河猴接种CCR5嗜性SHIVSF162P4。免疫后0、7、14、21、35、56、180天，用实时荧光定量聚合酶链式反应检测外周血中CCL3、CCL4、CCL5基因的表达水平。此外，还选择了一组感染CXCR4的SHIVKu1感染猕猴的样本，目的是比较两种SHIV在CC趋化因子下调方面的差异。从SHIVSF162P4感染的动物采集的肠道相关淋巴组织(GALT)也进行了流式细胞术和共聚焦显微镜检测，以证实基因表达的结果。可以预测，在感染SHIVKu1的猕猴中，在PID14处观察到的病毒载量和CD4T细胞损失比感染SHIVSF162P4的猕猴更高。CC-趋化因子基因的表达在原发期(PID7-21)也有下降，但在慢性(PID180)阶段没有下降。结果表明，在感染急性期，SHIVSF162P4对CC-趋化因子基因表达的下调幅度大于SHIVKu1(p0.05)，且这种下调与CD4T细胞耗竭不平行。对CC-趋化因子增强免疫调节剂的评价，如合成的CpG-寡核苷酸，可以在未来的HIV疫苗研究中探索。

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.