Coexpression Network Analysis of Benign and Malignant Phenotypes of SIV-Infected Sooty Mangabey and Rhesus Macaque
Zhao-Wan Yang1, Yan-Hua Jiang1, Chuang Ma2
1Hubei Bioinformatics and Molecular Imaging Key Laboratory, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.
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.
Insights
This study reveals that simian immunodeficiency virus (SIV) infection causes distinct gene expression changes in sooty mangabeys (nonprogression) versus rhesus macaques (progression to AIDS), linked to gut and mitochondrial health.
Area of Science:
- Immunology
- Genomics
- Virology
Background:
- Simian immunodeficiency virus (SIV) infection presents distinct clinical outcomes in different primate species.
- Sooty mangabeys (SMs) typically do not progress to AIDS (benign phenotype, BEN+), while rhesus macaques (RMs) progress to AIDS (malignant phenotype, MAL+).
- Understanding the molecular basis of these divergent SIV infection phenotypes is crucial for AIDS pathogenesis research.
Purpose of the Study:
- To investigate the differences in gene coexpression networks (GCNs) between SIV-infected SMs and RMs.
- To identify specific enriched genes and pathways (EGPs) associated with benign (BEN+) and malignant (MAL+) SIV infection phenotypes.
- To explore the role of exo- and endosymbiotic imbalances in SIV pathogenesis.
Main Methods:
- Integrated dual positive-negative connectivity (DPNC) analysis of GCNs using publicly available microarray gene expression data from SIV-infected SMs and RMs.
- Analysis of peripheral blood samples at multiple time points post-SIV infection.
- Identification and characterization of differentially expressed hub genes and associated pathways.
Main Results:
- Significant differences in DPNC values and GCN changes were observed between SIV-infected SMs and RMs.
- The MAL+ phenotype in RMs is associated with EGPs including the ubiquitin proteasome system, p53, and mitochondrial signaling, with sole mitochondrial dysfunction noted in RMs.
- Specific BEN+ EGPs in SMs include interferon signaling and DNA damage response pathways; mixed phenotypes involve PRR-activated signaling pathways.
- Hub genes LGALS8 and IL-17RA, related to gut barrier function and microbiota homeostasis, were differentially expressed, suggesting an exo-endo symbiotic imbalance (EESI).
Conclusions:
- Distinct molecular mechanisms underlie benign and malignant SIV infection phenotypes in different primate species.
- Mitochondrial dysfunction and gut dysbiosis (EESI) are implicated in SIV/HIV pathogenesis.
- Further research into exo-endo symbiotic balance (EESB) mechanisms could yield novel interventions for AIDS control.
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