title: Intact type I Interferon production and IRF7 function in sooty mangabeys.
abstract: 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 SIV(mac239) 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.
authors.affiliation: Divison of Microbiology and Immunology, Emory Vaccine Center, Yerkes National Primate Research Center, Atlanta, Georgia, United States of America. sbosing@emory.edu
authors.forename: Steven E
authors.initials: SE
authors.lastname: Bosinger
authors.forename: Zachary P
authors.initials: ZP
authors.lastname: Johnson
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Folkner
authors.forename: Nirav
authors.initials: N
authors.lastname: Patel
authors.forename: Tayebeh
authors.initials: T
authors.lastname: Hashempour
authors.forename: Simon P
authors.initials: SP
authors.lastname: Jochems
authors.forename: Perla M
authors.initials: PM
authors.lastname: Del Rio Estrada
authors.forename: Mirko
authors.initials: M
authors.lastname: Paiardini
authors.forename: Rongtuan
authors.initials: R
authors.lastname: Lin
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Vanderford
authors.forename: John
authors.initials: J
authors.lastname: Hiscott
authors.forename: Guido
authors.initials: G
authors.lastname: Silvestri
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics / Q000276:immunology; D019943:Amino Acid Substitution; D000818:Animals; D002467:Cell Nucleus / Q000235:genetics / Q000276:immunology*; D016665:Cercocebus atys; D004252:DNA Mutational Analysis; D003713:Dendritic Cells / Q000276:immunology / Q000821:virology; D005091:Exons / Q000235:genetics / Q000276:immunology; D005260:Female; D015658:HIV Infections / Q000235:genetics / Q000276:immunology; D015497:HIV-1 / Q000235:genetics / Q000276:immunology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D050839:Interferon Regulatory Factor-7 / Q000235:genetics / Q000276:immunology*; D016898:Interferon-alpha / Q000235:genetics / Q000276:immunology*; D016899:Interferon-beta / Q000235:genetics / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000276:immunology* / Q000821:virology; D008297:Male; D020125:Mutation, Missense; D011804:Quinolines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D016097:Simian Acquired Immunodeficiency Syndrome / Q000235:genetics / Q000276:immunology*; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000276:immunology*; D051199:Toll-Like Receptor 7 / Q000819:agonists / Q000235:genetics / Q000276:immunology
chemical_list: C547051:CL097 compound; D007093:Imidazoles; D050839:Interferon Regulatory Factor-7; D016898:Interferon-alpha; D011804:Quinolines; D012333:RNA, Messenger; D051199:Toll-Like Receptor 7; D016899:Interferon-beta