Divergent TLR7 and TLR9 signaling and type I interferon production distinguish pathogenic and nonpathogenic AIDS virus infections.
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-alpha 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.
Mandl
Judith N
JN
Graduate Program in Population Biology, Ecology and Evolution, Emory University, 1510 Clifton Road, Atlanta, Georgia 30322, USA.
Barry
Ashley P
AP
Vanderford
Thomas H
TH
Kozyr
Natalia
N
Chavan
Rahul
R
Klucking
Sara
S
Barrat
Franck J
FJ
Coffman
Robert L
RL
Staprans
Silvija I
SI
Feinberg
Mark B
MB
D000163:Acquired Immunodeficiency Syndrome / Q000276:immunology*; D000595:Amino Acid Sequence; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D016665:Cercocebus atys; D003713:Dendritic Cells / Q000276:immunology; D004198:Disease Susceptibility; D005260:Female; D006801:Humans; D016898:Interferon-alpha / Q000096:biosynthesis*; D007694:Killer Cells, Natural / Q000276:immunology; D008253:Macaca mulatta; D008297:Male; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000502:physiology; D054400:Receptors, CCR7 / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology*; D051199:Toll-Like Receptor 7 / Q000502:physiology*; D051217:Toll-Like Receptor 9 / Q000502:physiology*
D016898:Interferon-alpha; D016328:NF-kappa B; D054400:Receptors, CCR7; C495348:TLR7 protein, human; C495371:TLR9 protein, human; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9