Coexpression Network Analysis of Benign and Malignant Phenotypes of SIV-Infected Sooty Mangabey and Rhesus Macaque

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.

为探究两种极端猴免疫缺陷病毒（Simian Immunodeficiency Virus, SIV）感染表型的差异——即白眉猴（sooty mangabeys, SMs）感染后不进展为艾滋病（良性BEN: benign），与恒河猴（rhesus macaques, RMs）感染后进展为艾滋病（恶性MAL: malignant）——本研究基于美国国家生物技术信息中心（National Center for Biotechnology Information, NCBI）基因表达综合数据库（Gene Expression Omnibus, GEO）中的公开大数据集，对基因共表达网络（gene coexpression networks, GCN）开展了整合的双正负连接（dual positive-negative connectivity, DPNC）分析。本研究的微阵列基因表达数据集分别采集自SIV感染多个时间点下的白眉猴与恒河猴外周血。在SIV感染的白眉猴与恒河猴中，二者GCN的DPNC值变化存在显著差异。本研究鉴定出与三种SIV感染表型（BEN+、MAL+及混合表型BEN+/MAL+）相关的三类富集基因或通路（enriched genes or pathways, EGPs）。SIV感染恒河猴的MAL+表型特异性关联8类EGPs，涵盖蛋白质泛素化蛋白酶体系统、p53、颗粒酶A、颗粒酶B、polo样激酶、糖皮质激素受体、氧化磷酸化及线粒体信号通路。线粒体（内共生）功能障碍仅存在于恒河猴中。在SIV感染的白眉猴中，可观测到4类EGPs的BEN+特异性模式变化，涉及干扰素信号通路、BRCA1/DNA损伤应答通路、PKR/INF诱导通路及LGALS8基因。另有3类富集通路——PRR激活的IRF信号通路、RIG-I样受体通路及PRR通路——与恒河猴和白眉猴的SIV混合感染表型（BEN+/MAL+）相关，提示这些通路在宿主抗病毒感染免疫中发挥双重作用。对上述GCN中的枢纽基因（Hub genes）进行进一步分析后发现，LGALS8与IL-17RA基因在恒河猴与白眉猴中的表达存在显著差异；这两种基因可正向调控肠道黏膜屏障功能及肠道菌群（外共生）相关的免疫稳态。本研究数据表明，HIV/SIV感染过程中存在外共生（肠道菌群失调）与内共生（线粒体功能障碍）失衡（exo- and endo-symbiotic imbalance, EESI）。解析维持免疫稳态的外-内共生平衡（exo-endo symbiotic balance, EESB）机制，以及HIV/SIV感染中的EESI问题，或可助力我们更深入地理解艾滋病的发病机制，并开发出用于合理防控该病的新型干预手段。