Systems biology of natural simian immunodeficiency virus infections - PubMed (original) (raw)

Review

Systems biology of natural simian immunodeficiency virus infections

Steven E Bosinger et al. Curr Opin HIV AIDS. 2012 Jan.

Abstract

Purpose of review: A key factor driving AIDS-associated immunopathogenesis is chronic immune activation. Simian immunodeficiency virus (SIV) infection of African natural host species leads to high viremia, but low immune activation and absence of disease. Considerable progress in our understanding of pathological immune activation has come from comparative studies of SIV infection in pathogenic Asian macaque species and natural hosts. The focus of this review is to highlight recent work on the natural host model using high-throughput genomics.

Recent findings: Several groups have independently conducted microarray gene expression profiling comparing in-vivo SIV infection in natural and non-natural hosts. A consistent finding between these studies is that both pathogenic SIV infection of macaques and nonpathogenic infections of natural hosts have strong induction of interferon-stimulated genes (ISGs) early on, but a key difference was that natural hosts down-modulated the interferon response rapidly after acute infection. The development of new genome-based resources for further study of the natural host model is discussed.

Summary: Initial efforts using high-throughput biology to study SIV infection of natural hosts have effectively identified the ability of natural hosts to resolve interferon responses and immune activation. Further application of 'omic-based technologies coupled with integrative systems-based analysis should continue to yield progress.

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Figures

Figure 1

Figure 1. Systems biology strategy to identify regulatory mechanisms controlling the resolution of interferon responses in natural host species

pDCs have been implicated as a the predominant source of interferon production in lymph nodes of acutely infected SMs and AGMs [32]. (A) Transcriptional profiles of pDCs from natural and non-natural hosts activated over time with endogenous strains of SIV can be used to identify in a longitudinal analysis waves of genes expression and early activating ‘affector’ genes (i.e. signaling molecules; transcription factors) from ‘late’ effector genes. The ability of pDCs to suppress interferon expression despite chronic viremia suggest an epigenetic mechanism, and deep sequencing can be used to profile epigenetic modifications in pDCs before and after SIV exposure. The genome sequence of AGMs and SMs can be leveraged against epigenetic and transcriptome data to probe for species specific variation in the regulatory regions of genes with differential epigenetic/transcriptional profiles. (B) Importantly, potential candidates for negative feedback of interferon signaling in natural host species may not be readily identified as differential on highthroughput screens. Detailed reconstruction of gene networks, boolean and enrichment analysis of genes with sequence variation/differential behavior between natural and pathogenic hosts, kinetic modeling of transcription and correlation with IFNα/β production can be integrated to predict potential candidates and map biologically meaningful divergence in innate signaling. (C) Prioritized candidates can be perturbed in vitro using gene-knockdown techniques and assayed for their impact on prolonged interferon production. Candidates can also be examined using comparative in vivo study of SIV infected NHPs.

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