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 8

Systems biology identification of genes associated with immune activation in SIVmac239-infected RMs.

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Systems biology identification of genes associated with immune activatio...
(A) Pearson’s correlation of CD8+Ki-67+ fraction with MKI67 gene expression in SIVmac239-infected RMs. Peripheral blood Ki-67+CD8+% was assessed using the gating strategy outlined in B and was correlated with MKI67 mRNA log10 intensity in peripheral blood using Pearson’s correlation (false discovery rate corrected; P < 0.00106). (B) Representative density plot of flow cytometry analysis for expression of Ki-67+ on gated CD3+CD8+ T cells in PBMCs of SIVmac239-infected RMs. The numbers denote the percentage of gated cells, indicating the fraction of CD3+ T cells expressing CD4 or CD8 (left panels) or the fraction of CD3+CD8+ T cells expressing Ki-67 (right panels) from a time point prior to SIV infection and from day 31 after infection in the same animal. (C) Longitudinal expression profile of Ki-67 protein on CD3+CD8+ T cells as measured by flow cytometry; error bars indicate SEM. (D) MIK67 mRNA as measured by microarray. MKI67 gene expression is the average ratio of gene expression relative to preinfected samples. (E) Longitudinal profiles of 4 genes whose expression significantly correlated with CD8+Ki-67+ percentage in peripheral blood and identified in the literature as related to immune activation, CD8+ T cell exhaustion, or HIV pathogenesis. (F) Model of immunomodulation during SIV infection of natural hosts and during pathogenic infection, demonstrating differences in ISG induction and immunoregulatory gene expression; details in text.