Related Experiment Video
Updated: May 8, 2026
A High Resolution Method to Monitor Phosphorylation-dependent Activation of IRF3
Published on: January 24, 2016
Intact type I Interferon production and IRF7 function in sooty mangabeys
Steven E Bosinger1, Zachary P Johnson, Kathryn A Folkner
1Divison of Microbiology and Immunology, Emory Vaccine Center, Yerkes National Primate Research Center, Atlanta, Georgia, United States of America. sbosing@emory.edu
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.
Insights
Sooty mangabeys (SMs) resist AIDS from SIV infection due to intact, not muted, interferon-alpha (IFN-α) responses. Contrary to prior beliefs, SM IRF7 and IFN-α signaling are functional, explaining their AIDS resistance.
Area of Science:
- Immunology
- Virology
- Primate Models
Background:
- Sooty mangabeys (SMs) naturally control Simian Immunodeficiency Virus (SIV) infection without developing AIDS, unlike humans and rhesus macaques (RMs).
- Previous research suggested attenuated interferon-alpha (IFN-α) responses, linked to Interferon Regulatory Factor-7 (IRF7) variations in SMs, contribute to this non-pathogenic SIV infection.
- Conflicting studies indicate robust IFN-α responses and Interferon Stimulated Genes (ISGs) upregulation in acutely SIV-infected SMs, questioning the 'muted response' hypothesis.
Purpose of the Study:
- To investigate the role of reported IRF7 amino acid substitutions in SMs concerning their non-pathogenic SIV infection.
- To re-evaluate the hypothesis that 'muted' IFN-α responses protect SMs from developing AIDS.
- To compare IFN-α and IRF7 signaling pathways in SMs with those in RMs and humans.
Main Methods:
- Sequencing of all IRF7 exons in 16 SM breeders and variable exons in 177 additional animals.
- Functional assays using recombinant SM IRF7 to assess nuclear translocation and transcriptional activity.
- In vitro stimulation of SM peripheral blood mononuclear cells (PBMCs) with TLR7 agonist CL097 or SIV(mac239) to measure IFN-α/IFN-β mRNA and pDC IFN-α production.
Main Results:
- The previously reported Ser-Gly substitution at position 191 in SM IRF7 was identified as a sequencing error.
- Other reported IRF7 substitutions were found to be minor alleles, and recombinant SM IRF7 showed no functional defects.
- Stimulated SM PBMCs exhibited robust induction of IFN-α and IFN-β mRNA (500-800 fold) and significant IFN-α production by pDCs, comparable to RMs and humans.
Conclusions:
- IFN-α and IRF7 signaling pathways in sooty mangabeys are largely intact and functional.
- The previously proposed 'muted' IFN-α response mechanism is not responsible for AIDS resistance in SIV-infected SMs.
- Minor differences in IFN-α/IRF7 signaling between SMs and RMs are unlikely to explain the distinct disease outcomes of SIV infection.
Related Concept Videos
01:30Inhibitors of Viral Protein Synthesis
01:23RNA Interference
This process occurs naturally in cells, often through the activity of genomically-encoded microRNAs. Researchers can take advantage of this mechanism by introducing synthetic RNAs to deactivate specific genes for research or therapeutic purposes. For example, RNAi could be used...
01:23RNA Interference
This process occurs naturally in cells, often through the activity of genomically-encoded microRNAs. Researchers can take advantage of this mechanism by introducing synthetic RNAs to deactivate specific genes for research or therapeutic purposes. For example, RNAi could be used...
02:15Experimental RNAi
02:30siRNA - Small Interfering RNAs
In the cytoplasm, siRNA is processed from a double-stranded RNA, which comes from either endogenous DNA transcription or exogenous sources like a virus. This double-stranded RNA is then cleaved by the ATP-dependent...
01:29Immune Response Against Viral Pathogens
NK Cells
NK cells are a crucial part of our innate immune system, acting as the first line of defense against viral infections. These cells can recognize and kill infected cells without prior exposure to the virus, effectively slowing down the spread of infection. Additionally, NK cells produce proinflammatory...