HOST SPECIFIC RESPONSES IN SIV-INDUCED HEMATOSUPPRESSION

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。 本研究旨在比较猴免疫缺陷病毒(SIV)感染恒河猴(RMS)和黑尾猴(SMS)时，骨髓和其他免疫学部位的血液学和免疫学功能缺陷。 作为这项研究的一部分，并为了阐明SIV感染SMS良性表型的机制，我们使用高密度寡核苷酸芯片纵向评估了SIV感染的SM和RMS中宿主基因的表达。我们发现，SIV的急性感染与强健的先天免疫反应一致相关，包括干扰素刺激基因(ISGs)的广泛上调。虽然SMS表现出快速的ISG表达和免疫激活，但在RMS中这两种反应都是慢性观察到的。系统生物学分析表明，在SIV感染的RMS中，T细胞耗竭的标志物LAG3的表达与免疫激活有关，但与SM无关。 我们的发现表明，主动免疫调节机制，而不是内在减弱的先天免疫反应，是慢性感染SIV的SMS低水平免疫激活特征的基础。我们希望这项研究将为治疗HIV感染者的慢性异常免疫激活提供有用的信息。

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. This study is focused on comparative studies of the defects in the hematologic and immunological function of the bone marrow as well as other immunological sites during pathogenic and non-pathogenic Simian Immunodeficiency Virus (SIV) infections of rhesus macaques (RMs) and sooty mangabeys (SMs), respectively. As part of this study, and to elucidate the mechanisms underlying the benign phenotype of SIV infection of SMs, we have used high-density oligonucleotide microarrays to longitudinally assess host gene expression in SIV-infected SMs and RMs. We found that acute SIV infection of SMs was consistently associated with a robust innate immune response, including widespread upregulation of IFN-stimulated genes (ISGs). While SMs exhibited a rapid resolution of ISG expression and immune activation, both responses were observed chronically in RMs. Systems biology analysis indicated that expression of LAG3, a marker of T cell exhaustion, correlated with immune activation in SIV-infected RMs but not SMs. Our findings suggest that active immune regulatory mechanisms, rather than intrinsically attenuated innate immune responses, underlie the low levels of immune activation characteristic of SMs chronically infected with SIV. We are hopeful that this study will provide information useful in treating the chronic aberrant immune activation of HIV-infected humans.