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

Authors

Steven E. Bosinger, University of Pennsylvania School of Medicine, University Health NetworkFollow
Qingsheng Li, University of Nebraska - LincolnFollow
Shari N. Gordon, University of Pennsylvania School of MedicineFollow
Nichole R. Klatt, University of Pennsylvania School of Medicine
Lijie Duan, University of MinnesotaFollow
Luoling Xu, University Health Network
Nicholas Francella, University of Pennsylvania School of Medicine
Abubaker Sidahmed, University Health Network
Anthony J. Smith, University of MinnesotaFollow
Elizabeth M. Cramer, University of Pennsylvania School of Medicine
Ming Zeng, University of Minnesota
David Masopust, University of Minnesota
John V. Carlis, University of Minnesota
Longsi Ran, University Health Network
Thomas H. Vanderford, University of Pennsylvania School of Medicine
Mirko Paiardini, University of Pennsylvania School of Medicine
R. Benjamin Isett, University of Pennsylvania School of Medicine
Don A. Baldwin, University of Pennsylvania School of Medicine
James G. Else, Yerkes National Primate Research Center, Emory University
Silvija I. Staprans, Merck Vaccines and Infectious Diseases
Guido Silvestri, University of Pennsylvania School of Medicine; Yerkes National Primate Research Center, Emory University
Ashley T. Hasse, University of Minnesota
David J. Kelvin, University Health Network; International Institute of Infection and Immunity, Shantou University Medical College

Date of this Version

12-2009

Document Type

Article

Citation

J. Clin. Invest. 119:3556–3572 (2009). doi:10.1172/JCI40115

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.