Article abstract
Nature Medicine 14, 1077 - 1087 (2008)
Published online: 14 September 2008 | doi:10.1038/nm.1871
Divergent TLR7 and TLR9 signaling and type I interferon production distinguish pathogenic and nonpathogenic AIDS virus infections
Judith N Mandl1,2,6, Ashley P Barry2,6, Thomas H Vanderford2, Natalia Kozyr2, Rahul Chavan2, Sara Klucking2, Franck J Barrat3, Robert L Coffman3, Silvija I Staprans2,4,5 & Mark B Feinberg2,4,5
Abstract
Pathogenic HIV infections of humans and simian immunodeficiency virus (SIV) infections of rhesus macaques are characterized by generalized immune activation and progressive CD4+ T cell depletion. In contrast, natural reservoir hosts for SIV, such as sooty mangabeys, do not progress to AIDS and show a lack of aberrant immune activation and preserved CD4+ T cell populations, despite high levels of SIV replication. Here we show that sooty mangabeys have substantially reduced levels of innate immune system activation in vivo during acute and chronic SIV infection and that sooty mangabey plasmacytoid dendritic cells (pDCs) produce markedly less interferon-
in response to SIV and other Toll-like receptor 7 and 9 ligands ex vivo. We propose that chronic stimulation of pDCs by SIV and HIV in non-natural hosts may drive the unrelenting immune system activation and dysfunction underlying AIDS progression. Such a vicious cycle of continuous virus replication and immunopathology is absent in natural sooty mangabey hosts.
- Graduate Program in Population Biology, Ecology and Evolution, Emory University, 1510 Clifton Road, Atlanta, Georgia 30322, USA.
- Emory Vaccine Center and Yerkes National Primate Research Center, 954 Gatewood Road, Atlanta, Georgia 30329, USA.
- Dynavax Technologies, 2929 Seventh Street, Berkeley, California 94710, USA.
- Department of Microbiology and Immunology and Department of Medicine, Emory University School of Medicine, 954 Gatewood Road, Atlanta, Georgia 30329, USA.
- Current address: Merck Vaccines and Infectious Diseases, Merck & Co., Inc., WP97-A337, 770 Sumneytown Pike, PO Box 4, West Point, Pennsylvania 19486, USA.
- These authors contributed equally to this work.
Correspondence to: Mark B Feinberg2,4,5 e-mail: mark_feinberg@merck.com
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