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

Abstract

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.

Infectomic Insights into the Roles of Exosymbiosis-Endosymbiosis Imbalance (EESI) in HIV-1 and SIV Infections

“…It has been proposed that the Exo-Endo Sym (EES) balance is essential for health and that the EES imbalance (EESI) plays a central role in the pathogenesis of infectious diseases, including AIDS caused by HIV-1 and SIV [8]. This notion is further supported by our infectomic analysis of the two extreme phenotypes of SIV infection [7].…”

“…Point mutations and deletion of mitochondrial DNA can lead to decreasing HIV-1 infection [16]. Mitochondria play a key role in the production of energy and the through infectomic studies of the Sym/Pat phenotypes of HIV and SIV infections [6][7][8]19]. The Pat+ phenotype in SIV-infected RMs is specifically associated with disorders in the protein ubiquitin proteasome system, p53, granzyme A, gramzyme B, polo-like kinase, Glucocorticoid receptor, oxidative phosyphorylation and mitochondrial signaling.…”

“…Pathogenesis, prevention, treatment and cure of HIV-1 infection remain one of the greatest challenges in modern medicine since the discovery of this disease 1981 [4,5]. There are usually two basic phenotypes [pathogenesis (Pat) and symbiosis (Sym)] of microbial infection including human HIV/AIDS [6,7]. However, the conventional wisdom places emphasis on the pathogenic process-namely antagonism-rather than mutualism [1].…”

“…However, the conventional wisdom places emphasis on the pathogenic process-namely antagonism-rather than mutualism [1]. Two extreme phenotypes are present in both HIV-1 and SIV infections, including slow or rapid progression to AIDS (Pat) in a majority of the infected human subjects and the non-natural primate host (i.e., rhesus macaques, RMs), and nonprogression to AIDS (Sym) in a minority of the infected people and the natural primate hosts (i.e., sooty mangabeys, SMs) [7]. Infectomic insight into the differences in phenotypes of HIV-1/SIV infections has been essential for uncovering this relationship and conquering AIDS.…”

Resources for functional genomic studies of health and development in nonhuman primates

“…Catalogs of predicted deleterious variation and human pathogenic variants segregating in NHP populations, especially those available in research centers, provide natural models for studies of gene functionalities within and between species. Beyond these reference resources, there are many publicly available datasets, which have been created to address specific biological questions, for example, responses to specific conditions, including social status (Lea, Altmann, Alberts, & Tung, ; Massart et al, ; Tung et al, ) or pathogens (Rotger et al, ; Yang et al, ).…”