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Comparative transcriptomics of extreme phenotypes of human HIV-1 infection and SIV infection in sooty mangabey and rhesus macaque.

ABSTRACT: High levels of HIV-1 replication during the chronic phase of infection usually correlate with rapid progression to severe immunodeficiency. However, a minority of highly viremic individuals remains asymptomatic and maintains high CD4? T cell counts. This tolerant profile is poorly understood and reminiscent of the widely studied nonprogressive disease model of SIV infection in natural hosts. Here, we identify transcriptome differences between rapid progressors (RPs) and viremic nonprogressors (VNPs) and highlight several genes relevant for the understanding of HIV-1-induced immunosuppression. RPs were characterized by a specific transcriptome profile of CD4? and CD8? T cells similar to that observed in pathogenic SIV-infected rhesus macaques. In contrast, VNPs exhibited lower expression of interferon-stimulated genes and shared a common gene regulation profile with nonpathogenic SIV-infected sooty mangabeys. A short list of genes associated with VNP, including CASP1, CD38, LAG3, TNFSF13B, SOCS1, and EEF1D, showed significant correlation with time to disease progression when evaluated in an independent set of CD4? T cell expression data. This work characterizes 2 minimally studied clinical patterns of progression to AIDS, whose analysis may inform our understanding of HIV pathogenesis.

SUBMITTER: Rotger M

PROVIDER: S-EPMC3104754 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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Comparative transcriptomics of extreme phenotypes of human HIV-1 infection and SIV infection in sooty mangabey and rhesus macaque.

Rotger Margalida M Dalmau Judith J Rauch Andri A McLaren Paul P Bosinger Steven E SE Martinez Raquel R Sandler Netanya G NG Roque Annelys A Liebner Julia J Battegay Manuel M Bernasconi Enos E Descombes Patrick P Erkizia Itziar I Fellay Jacques J Hirschel Bernard B Miró Jose M JM Palou Eduard E Hoffmann Matthias M Massanella Marta M Blanco Julià J Woods Matthew M Günthard Huldrych F HF de Bakker Paul P Douek Daniel C DC Silvestri Guido G Martinez-Picado Javier J Telenti Amalio A

The Journal of clinical investigation 20110509 6

High levels of HIV-1 replication during the chronic phase of infection usually correlate with rapid progression to severe immunodeficiency. However, a minority of highly viremic individuals remains asymptomatic and maintains high CD4⁺ T cell counts. This tolerant profile is poorly understood and reminiscent of the widely studied nonprogressive disease model of SIV infection in natural hosts. Here, we identify transcriptome differences between rapid progressors (RPs) and viremic nonprogressors (V ...[more]

PMID: 21555857

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Project description: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.

Dataset Information

Comparative transcriptomics of extreme phenotypes of human HIV-1 infection and SIV infection in sooty mangabey and rhesus macaque.

Publications

Comparative transcriptomics of extreme phenotypes of human HIV-1 infection and SIV infection in sooty mangabey and rhesus macaque.

Similar Datasets

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