Simian Immunodeficiency Virus-Induced Alterations in Monocyte Production of Tumor Necrosis Factor Alpha Contribute to Reduced Immune Activation in Sooty Mangabeys

• Type of Material: Article
• Authors: Kiran D. Mir, Seattle Biomedical Research Institute; Steven Bosinger, Emory University; Melanie Gasper, Seattle Biomedical Research Institute; On Ho, University of Washington; James Else, Emory University; Jason M. Brenchley, NIAID; David J. Kelvin, University of Toronto; Guido Silvestri, Emory University; Shiu-lok Hu, University of Washington; Donald L. Sodora, Seattle Biomedical Research Institute
• Language: English
• Date: 2012-07-01
• Publisher: American Society for Microbiology
• Publication Version: Final Published Version
• Copyright Statement: © 2012, American Society for Microbiology. All Rights Reserved.
• Final Published Version (URL): http://dx.doi.org/10.1128/JVI.06813-11
• Title of Journal or Parent Work: Journal of Virology
• ISSN: 0022-538X
• Volume: 86
• Issue: 14
• Start Page: 7605
• End Page: 7615
• Grant/Funding Information: Work was supported by the NIH, including grants to the Yerkes Primate Center (P51-RR00165), the University of Washington Center for AIDS Research (CFAR) (P30 AI027757;), M. Gasper (T32AI083203;), and D. Sodora (R56 AI087468; and R01 DE017541), and by the Pendleton Trust.
• Keywords: Virology; INTERFERON RESPONSES; Life Sciences & Biomedicine; PATHOGENIC INFECTION; ANTI-TNF; DOWN-REGULATION; RHESUS MACAQUES; MICROBIAL TRANSLOCATION; HIV-1 INFECTION; NATURAL HOSTS; Science & Technology; T-CELL DEPLETION; VIROLOGY; NONPATHOGENIC SIV INFECTION
• Research Categories: Health Sciences, Immunology; Health Sciences, Pathology

Abstract

Human immunodeficiency virus type 1 (HIV-1) infection is characterized by persistent viral replication in the context of CD4 + T cell depletion and elevated immune activation associated with disease progression. In contrast, simian immunodeficiency virus (SIV) infection of African-origin sooty mangabeys (SM) generally does not result in simian AIDS despite high viral loads and therefore affords a unique model in which to study the immunologic contributions to a nonpathogenic lentiviral disease outcome. A key feature of these natural SIV infections is the maintenance of low levels of immune activation during chronic infection. Our goal was to delineate the contribution of monocytes to maintaining low levels of immune activation in SIV-infected SM. Utilizing an ex vivo whole-blood assay, proinflammatory cytokine production was quantified in monocytes in response to multiple Toll-like receptor (TLR) ligands and a specific, significant reduction in the tumor necrosis factor alpha (TNF-α) response to lipopolysaccharide (LPS) was observed in SIV-infected SM. In contrast, monocytes from hosts of pathogenic infections (HIV-infected humans and SIV-infected Asian macaques) maintained a robust TNF-α response. In SIV-infected SM, monocyte TNF-α responses to low levels of LPS could be augmented by the presence of plasma from uninfected control animals. The impact of LPS-induced TNF-α production on immune activation was demonstrated in vitro, as TNF-α blocking antibodies inhibited downstream CD8 + T cell activation in a dose-dependent manner. These data demonstrate an association between nonpathogenic SIV infection of SM and a reduced monocyte TNF-α response to LPS, and they identify a role for monocytes in contributing to the suppressed chronic immune activation observed in these natural hosts. © 2012, American Society for Microbiology.