Global genomic analysis reveals rapid control of a robust innate response in SIV-infected sooty mangabeys
Steven E. Bosinger, … , Ashley T. Haase, David J. Kelvin
Steven E. Bosinger, … , Ashley T. Haase, David J. Kelvin
Published November 23, 2009
Citation Information: J Clin Invest. 2009;119(12):3556-3572. https://doi.org/10.1172/JCI40115.
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Research Article

Global genomic analysis reveals rapid control of a robust innate response in SIV-infected sooty mangabeys

Abstract

Natural SIV infection of sooty mangabeys (SMs) is nonprogressive despite chronic virus replication. Strikingly, it is characterized by low levels of immune activation, while pathogenic SIV infection of rhesus macaques (RMs) is associated with chronic immune activation. To elucidate the mechanisms underlying this intriguing phenotype, we used high-density oligonucleotide microarrays to longitudinally assess host gene expression in SIV-infected SMs and RMs. We found that acute SIV infection of SMs was consistently associated with a robust innate immune response, including widespread upregulation of IFN-stimulated genes (ISGs) in blood and lymph nodes. While SMs exhibited a rapid resolution of ISG expression and immune activation, both responses were observed chronically in RMs. Systems biology analysis indicated that expression of the lymphocyte inhibitory receptor LAG3, a marker of T cell exhaustion, correlated with immune activation in SIV-infected RMs but not SMs. Our findings suggest that active immune regulatory mechanisms, rather than intrinsically attenuated innate immune responses, underlie the low levels of immune activation characteristic of SMs chronically infected with SIV.

Authors

Steven E. Bosinger, Qingsheng Li, Shari N. Gordon, Nichole R. Klatt, Lijie Duan, Luoling Xu, Nicholas Francella, Abubaker Sidahmed, Anthony J. Smith, Elizabeth M. Cramer, Ming Zeng, David Masopust, John V. Carlis, Longsi Ran, Thomas H. Vanderford, Mirko Paiardini, R. Benjamin Isett, Don A. Baldwin, James G. Else, Silvija I. Staprans, Guido Silvestri, Ashley T. Haase, David J. Kelvin

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Figure 4

SMs and RMs exhibit distinct molecular signatures upon SIV infection.

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SMs and RMs exhibit distinct molecular signatures upon SIV infection. (A...
(A) Venn diagram indicating overlap of /probe sets with differential expression in SMs and RMs in response to SIV infection. (B) Heat map of 1025 probe sets induced in SIVsmm-infected SMs and/or SIVmac239-infected RMs. Chr, chronic. (C) Ontology enrichment comparison of SIV-inducible genes was performed using Ingenuity Pathway Analysis. Genes with significant differential expression at day 10 and day 180 in SIVsmm-infected SMs and SIVmac239-infected RMs (indicated by colored bars) were analyzed for annotation against all genes for a given function in the Ingenuity database using right-tailed Fisher’s exact test. A significance threshold of P = 0.05 is indicated by the horizontal line. (D) Heat map of 43 probe sets significantly induced by SIVsmm infection in SMs and judged significantly different between infection groups. The heat maps depict probe sets with the largest magnitude of gene-expression fold change and/or known function in immune responses, apoptosis, or cell cycle. For B and D, genes were organized in heat maps using hierarchical clustering as described in Figure 1 legend and in Supplemental Methods. “Chronic” refers to day 180 in the SIVsmm-infected SMs and RMs and day 184–224 in SIVmac239-infected RMs. Relative gene-expression changes are depicted by the color scales below heat maps. (E) Correlation between relative fold changes measured by microarray and qPCR. Each point represents the fold change of a single gene relative to day 0 for individual animals at a given time point; x and y axes are microarray and qPCR log10 fold changes, respectively. Number of XY pairs = 969. Pearson’s r correlation = 0.6614; 95% CI = 0.6244 to 0.6954; P < 0.0001 (2-tailed).