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. StapransGuido Silvestri, Ashley T. Haase, David J. Kelvin

Research output: Contribution to journalArticle

268 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)3556-3572
Number of pages17
JournalJournal of Clinical Investigation
Volume119
Issue number12
DOIs
StatePublished - Dec 1 2009

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Cercocebus atys
Macaca mulatta
Innate Immunity
Infection
Gene Expression
Systems Biology
Virus Replication
Oligonucleotide Array Sequence Analysis
Up-Regulation
Lymph Nodes
Lymphocytes
T-Lymphocytes
Phenotype

ASJC Scopus subject areas

  • Medicine(all)

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Global genomic analysis reveals rapid control of a robust innate response in SIV-infected sooty mangabeys. / Bosinger, Steven E.; Li, Qingsheng; Gordon, Shari N.; Klatt, Nichole R.; Duan, Lijie; Xu, Luoling; Francella, Nicholas; Sidahmed, Abubaker; Smith, Anthony J.; Cramer, Elizabeth M.; Zeng, Ming; Masopust, David; Carlis, John V.; Ran, Longsi; Vanderford, Thomas H.; Paiardini, Mirko; Isett, R. Benjamin; Baldwin, Don A.; Else, James G.; Staprans, Silvija I.; Silvestri, Guido; Haase, Ashley T.; Kelvin, David J.

In: Journal of Clinical Investigation, Vol. 119, No. 12, 01.12.2009, p. 3556-3572.

Research output: Contribution to journalArticle

Bosinger, SE, Li, Q, Gordon, SN, Klatt, NR, Duan, L, Xu, L, Francella, N, Sidahmed, A, Smith, AJ, Cramer, EM, Zeng, M, Masopust, D, Carlis, JV, Ran, L, Vanderford, TH, Paiardini, M, Isett, RB, Baldwin, DA, Else, JG, Staprans, SI, Silvestri, G, Haase, AT & Kelvin, DJ 2009, 'Global genomic analysis reveals rapid control of a robust innate response in SIV-infected sooty mangabeys', Journal of Clinical Investigation, vol. 119, no. 12, pp. 3556-3572. https://doi.org/10.1172/JCI40115
Bosinger, Steven E. ; Li, Qingsheng ; Gordon, Shari N. ; Klatt, Nichole R. ; Duan, Lijie ; Xu, Luoling ; Francella, Nicholas ; Sidahmed, Abubaker ; Smith, Anthony J. ; Cramer, Elizabeth M. ; Zeng, Ming ; Masopust, David ; Carlis, John V. ; Ran, Longsi ; Vanderford, Thomas H. ; Paiardini, Mirko ; Isett, R. Benjamin ; Baldwin, Don A. ; Else, James G. ; Staprans, Silvija I. ; Silvestri, Guido ; Haase, Ashley T. ; Kelvin, David J. / Global genomic analysis reveals rapid control of a robust innate response in SIV-infected sooty mangabeys. In: Journal of Clinical Investigation. 2009 ; Vol. 119, No. 12. pp. 3556-3572.
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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.",
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AU - Duan, Lijie

AU - Xu, Luoling

AU - Francella, Nicholas

AU - Sidahmed, Abubaker

AU - Smith, Anthony J.

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AU - Carlis, John V.

AU - Ran, Longsi

AU - Vanderford, Thomas H.

AU - Paiardini, Mirko

AU - Isett, R. Benjamin

AU - Baldwin, Don A.

AU - Else, James G.

AU - Staprans, Silvija I.

AU - Silvestri, Guido

AU - Haase, Ashley T.

AU - Kelvin, David J.

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N2 - 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.

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