Intact Type I Interferon Production and IRF7 Function in Sooty Mangabeys

PLoS Pathogens

Nirav Patel¹  Mirko Paiardini²  Rongtuan Lin²  Thomas H. Vanderford²  Guido Silvestri²  Tayebeh Hashempour²  Perla M. del Rio Estrada²  Steven E. Bosinger²  John Hiscott³  Zachary P. Johnson⁴  Simon P. Jochems⁴  Kathryn A. Folkner⁴ 

[1] Division of Cognitive and Developmental Biology, Yerkes National Primate Research Center, Atlanta, Georgia, United States of America;Divison of Microbiology and Immunology, Emory Vaccine Center, Yerkes National Primate Research Center, Atlanta, Georgia, United States of America;Lady Davis Institute-Jewish General Hospital, McGill University, Montreal, Quebec, Canada;Non-Human Primate Genomics Core, Yerkes National Primate Research Center, Robert W. Woodruff Health Sciences Center, Emory University, Atlanta, Georgia, United States of America

关键词: SIV;    Immune response;    Interferons;    Macaque;    Immune activation;    AIDS;    Amino acid substitution;    Transactivation;   

DOI  :  10.1371/journal.ppat.1003597

学科分类：生物科学（综合）

来源: Public Library of Science

【 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-α) 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-α responses are responsible for the benign nature of SIV infection in SMs. However, other studies indicated that acutely SIV-infected SMs show robust IFN-α 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-α 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-α and IFN-β mRNA, and levels of IFN-α production by pDCs similar to those of RMs or humans. These data establish that IFN-α 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.

【 授权许可】

CC BY