Intact Type I Interferon Production and IRF7 Function in Sooty Mangabeys

被引:30
作者
Bosinger, Steven E. [1 ,2 ]
Johnson, Zachary P. [2 ,3 ]
Folkner, Kathryn A. [1 ]
Patel, Nirav [2 ]
Hashempour, Tayebeh [1 ]
Jochems, Simon P. [1 ]
Estrada, Perla M. del Rio [1 ]
Paiardini, Mirko [1 ]
Lin, Rongtuan [4 ]
Vanderford, Thomas H. [1 ]
Hiscott, John [4 ,5 ]
Silvestri, Guido [1 ]
机构
[1] Yerkes Natl Primate Res Ctr, Emory Vaccine Ctr, Div Microbiol & Immunol, Atlanta, GA USA
[2] Emory Univ, Robert W Woodruff Hlth Sci Ctr, Nonhuman Primate Genom Core, Yerkes Natl Primate Res Ctr, Atlanta, GA 30322 USA
[3] Yerkes Natl Primate Res Ctr, Div Cognit & Dev Biol, Atlanta, GA USA
[4] McGill Univ, Jewish Gen Hosp, Lady Davis Inst, Montreal, PQ H3T 1E2, Canada
[5] Vaccine & Gene Therapy Inst Florida Port St Lucie, Port St Lucie, FL USA
来源
PLOS PATHOGENS | 2013年 / 9卷 / 08期
基金
美国国家卫生研究院;
关键词
CD4(+) T-CELLS; AFRICAN-GREEN MONKEYS; IMMUNODEFICIENCY VIRUS-INFECTION; PLASMACYTOID DENDRITIC CELLS; NONPATHOGENIC SIV INFECTION; TOLL-LIKE RECEPTORS; LENTIVIRAL INFECTIONS; MEDIATED SUPPRESSION; REGULATORY FACTOR-7; ANTIVIRAL RESPONSE;
D O I
10.1371/journal.ppat.1003597
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
In contrast to pathogenic HIV/SIV infections of humans and rhesus macaques (RMs), natural SIV infection of sooty mangabeys (SMs) is typically non-pathogenic despite high viremia. Several studies suggested that low immune activation and relative resistance of CD4+ central memory T-cells from virus infection are mechanisms that protect SMs from AIDS. In 2008 it was reported that plasmacytoid dendritic cells (pDCs) of SMs exhibit attenuated interferon-alpha (IFN-alpha) responses to TLR7/9 ligands in vitro, and that species-specific amino acid substitutions in SM Interferon Regulatory Factor-7 (IRF7) are responsible for this observation. Based on these findings, these authors proposed that "muted" IFN-alpha responses are responsible for the benign nature of SIV infection in SMs. However, other studies indicated that acutely SIV-infected SMs show robust IFN-alpha responses and marked upregulation of Interferon Stimulated Genes (ISGs). To investigate this apparent disparity, we first examined the role of the reported IRF7 amino acid substitutions in SMs. To this end, we sequenced all IRF7 exons in 16 breeders, and exons displaying variability (exons 2,3,5,6,7,8) in the remainder of the colony (177 animals). We found that the reported Ser-Gly substitution at position 191 was a sequencing error, and that several of the remaining substitutions represent only minor alleles. In addition, functional assays using recombinant SM IRF7 showed no defect in its ability to translocate in the nucleus and drive transcription from an IFN-alpha promoter. Furthermore, in vitro stimulation of SM peripheral blood mononuclear cells with either the TLR7 agonist CL097 or SIVmac239 induced an 500-800-fold induction of IFN-alpha and IFN-beta mRNA, and levels of IFN-alpha production by pDCs similar to those of RMs or humans. These data establish that IFN-alpha and IRF7 signaling in SMs are largely intact, with differences with RMs that are minor and unlikely to play any role in the AIDS resistance of SIV-infected SMs.
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