Department of Pathology and Laboratory Medicine, and Microbiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
J Clin Invest. 2009 Dec;119(12):3556-72. doi: 10.1172/JCI40115.
Natural SIV infection of sooty mangabeys (SMs) is nonprogressive despite chronic virus replication. Strikingly, it is characterized by low levels of immune activation, while pathogenic SIV infection of rhesus macaques (RMs) is associated with chronic immune activation. To elucidate the mechanisms underlying this intriguing phenotype, we 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) in blood and lymph nodes. 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 the lymphocyte inhibitory receptor 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.
尽管黑眉长尾猴（SM）中会发生自然发生的 SIV 感染，但这种感染不会进展。引人注目的是，其特征是免疫激活水平较低，而 SIV 对恒河猴（RMs）的致病性感染与慢性免疫激活有关。为了阐明这种有趣表型的机制，我们使用高密度寡核苷酸微阵列对 SIV 感染的 SM 和 RM 中的宿主基因表达进行了纵向评估。我们发现，SM 中的急性 SIV 感染始终与强烈的先天免疫反应相关，包括血液和淋巴结中广泛的 IFN 刺激基因（ISGs）上调。尽管 SM 中 ISG 表达和免疫激活迅速得到解决，但在 RM 中观察到这两种反应均呈慢性。系统生物学分析表明，淋巴细胞抑制受体 LAG3 的表达与 SIV 感染的 RM 中的免疫激活相关，但与 SM 无关，LAG3 是 T 细胞耗竭的标志物。我们的研究结果表明，在 SIV 慢性感染的 SM 中，固有免疫反应减弱并非免疫激活水平较低的唯一原因，主动的免疫调节机制可能也发挥了作用。
