Global genomic analysis reveals rapid control of a robust innate response in SIV-infected sooty mangabeys
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
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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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 1

Experimental design, viral load, and CD4+ T cell kinetics in SIV-infected SMs and RMs.

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Experimental design, viral load, and CD4+ T cell kinetics in SIV-infecte...
(A) Comparison of transcriptional profiles in peripheral blood induced by SIV infection was conducted in 5 SMs infected with SIVsmm to represent a nonpathogenic infection; 4 RMs inoculated with SIVsmm to compare infection of a nonnatural host with an isogenic virus; and 8 RMs infected with SIVmac239 to represent a classical, pathogenic infection. Arrows indicate SIV infection, vertical lines indicate RNA sampling time points, and crosses indicate LN biopsy time points. SIVsmm-infected SMs (blue line) and RMs (black line) were sampled at days –5, 3, 7, 10, 14, and 30 (preinfection and acute) and 180 (chronic) after infection; SIVmac239-infected RMs (red line) were sampled at days –35, 9, 14, and 31 (preinfection and acute) and days 184–224 (chronic) after infection and were treated with ART and OKT8F mAb after day 50 after infection (see text and Methods for details), as indicated by the dashed line. During the chronic phase of infection in the SIVmac239 group, samples were collected at least 30 days after the last in vivo manipulation (i.e., ART and CD8+ lymphocyte depletion). (B) Longitudinal assessment of plasma viral load (RNA copies/ml plasma) in SMs (n = 5) and RMs (n = 4) infected with SIVsmm and RMs (n = 8) infected with SIVmac239. (C) Longitudinal analysis of the absolute numbers of CD3+CD4+ T lymphocytes per ml in peripheral blood, determined by flow cytometry. In B and C, the x axis shows time after SIV infection, and error bars indicate SEM.