Yang Zhao-Wan, Jiang Yan-Hua, Ma Chuang, Silvestri Guido, Bosinger Steven E, Li Bai-Lian, Jong Ambrose, Zhou Yan-Hong, Huang Sheng-He
Hubei Bioinformatics and Molecular Imaging Key Laboratory, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.
Saban Research Institute of Children's Hospital Los Angeles, Department of Pediatrics, University of Southern California, Los Angeles, California, United States of America.
PLoS One. 2016 Jun 9;11(6):e0156170. doi: 10.1371/journal.pone.0156170. eCollection 2016.
To explore the differences between the extreme SIV infection phenotypes, nonprogression (BEN: benign) to AIDS in sooty mangabeys (SMs) and progression to AIDS (MAL: malignant) in rhesus macaques (RMs), we performed an integrated dual positive-negative connectivity (DPNC) analysis of gene coexpression networks (GCN) based on publicly available big data sets in the GEO database of NCBI. The microarray-based gene expression data sets were generated, respectively, from the peripheral blood of SMs and RMs at several time points of SIV infection. Significant differences of GCN changes in DPNC values were observed in SIV-infected SMs and RMs. There are three groups of enriched genes or pathways (EGPs) that are associated with three SIV infection phenotypes (BEN+, MAL+ and mixed BEN+/MAL+). The MAL+ phenotype in SIV-infected RMs is specifically associated with eight EGPs, including the protein ubiquitin proteasome system, p53, granzyme A, gramzyme B, polo-like kinase, Glucocorticoid receptor, oxidative phosyphorylation and mitochondrial signaling. Mitochondrial (endosymbiotic) dysfunction is solely present in RMs. Specific BEN+ pattern changes in four EGPs are identified in SIV-infected SMs, including the pathways contributing to interferon signaling, BRCA1/DNA damage response, PKR/INF induction and LGALS8. There are three enriched pathways (PRR-activated IRF signaling, RIG1-like receptor and PRR pathway) contributing to the mixed (BEN+/MAL+) phenotypes of SIV infections in RMs and SMs, suggesting that these pathways play a dual role in the host defense against viral infections. Further analysis of Hub genes in these GCNs revealed that the genes LGALS8 and IL-17RA, which positively regulate the barrier function of the gut mucosa and the immune homeostasis with the gut microbiota (exosymbiosis), were significantly differentially expressed in RMs and SMs. Our data suggest that there exists an exo- (dysbiosis of the gut microbiota) and endo- (mitochondrial dysfunction) symbiotic imbalance (EESI) in HIV/SIV infections. Dissecting the mechanisms of the exo-endo symbiotic balance (EESB) that maintains immune homeostasis and the EESI problems in HIV/SIV infections may lead to a better understanding of the pathogenesis of AIDS and the development of novel interventions for the rational control of this disease.
为了探究两种极端的猴免疫缺陷病毒（SIV）感染表型之间的差异，即乌黑白眉猴（SMs）不发展为获得性免疫缺陷综合征（AIDS，BEN：良性）和恒河猴（RMs）发展为AIDS（MAL：恶性），我们基于美国国立医学图书馆（NCBI）基因表达综合数据库（GEO）中的公开大数据集，对基因共表达网络（GCN）进行了整合的双正负连通性（DPNC）分析。基于微阵列的基因表达数据集分别来自SIV感染几个时间点的SMs和RMs的外周血。在SIV感染的SMs和RMs中，观察到GCN变化在DPNC值上有显著差异。有三组富集基因或通路（EGPs）与三种SIV感染表型（BEN +、MAL +和混合的BEN + / MAL +）相关。SIV感染的RMs中的MAL +表型与八个EGPs特异性相关，包括蛋白质泛素蛋白酶体系统、p53、颗粒酶A、颗粒酶B、polo样激酶、糖皮质激素受体、氧化磷酸化和线粒体信号传导。线粒体（内共生）功能障碍仅存在于RMs中。在SIV感染的SMs中，在四个EGPs中鉴定出特定的BEN +模式变化，包括有助于干扰素信号传导、BRCA1 / DNA损伤反应、PKR / INF诱导和LGALS8的通路。有三个富集通路（模式识别受体激活的干扰素调节因子信号传导、维甲酸诱导基因I样受体和模式识别受体通路）促成了RMs和SMs中SIV感染的混合（BEN + / MAL +）表型，这表明这些通路在宿主抗病毒感染防御中起双重作用。对这些GCN中的中心基因进行进一步分析发现，正向调节肠道黏膜屏障功能和与肠道微生物群（外共生）的免疫稳态的基因LGALS8和IL - 17RA在RMs和SMs中有显著差异表达。我们的数据表明，在HIV / SIV感染中存在外（肠道微生物群失调）和内（线粒体功能障碍）共生失衡（EESI）。剖析维持免疫稳态的外 - 内共生平衡（EESB）机制以及HIV / SIV感染中的EESI问题，可能有助于更好地理解AIDS的发病机制，并开发合理控制该疾病的新型干预措施。
