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 3

Gene-expression profile of the immune response to SIV infection in SMs.

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Gene-expression profile of the immune response to SIV infection in SMs. ...
(A) Ontology profiling of 428 probe sets significantly altered by SIV infection in SMs was based on gene ontology annotations retrieved from the DAVID Bioinformatics Database. Columns represent the number of genes in each ontology cluster listed below the x axis. Enrichment scores were calculated using the human genome as a background. (B) Hierarchical clustering of 428 genes significantly regulated by SIV infection in SMs was performed as described in Figure 1 legend. Clustering was performed on the average of log10 ratios of gene expression relative to levels before infection; fold changes were calculated by subtracting the log10 intensity preinfected measurement from after-infection measurement for individual animals prior to calculating the average. The dendrogram is not shown. (C) PCA of log10 intensity measurements of 428 differentially expressed probe sets. Colored circles represent data set for individual SMs at the time points indicated in the key. Ellipses are centered on the median of the following time points: days 0, 10, and 14. (D) Heat maps of selected innate immunity, adaptive immunity, apoptosis, and cell-cycle regulating genes with differential expression in SIV-infected SMs. Genes were categorized based on annotation in DAVID, Entrez Gene (http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene), and Ingenuity Pathway Assist databases and on described function in the literature. Genes covered by multiple probe sets on the array are represented by the highest intensity. Genes were clustered as described in Figure 1 legend. Color scale is shown at bottom and ranges from 2-fold downregulated to 5-fold upregulated.