Triggering TLR7 in mice induces immune activation and lymphoid system disruption, resembling HIV-mediated pathology.
Chronic immune activation is a major cause for progressive immunodeficiency in human immunodeficiency virus type-1 (HIV) infection. The underlying trigger, however, remains largely unknown. HIV single-stranded RNA is a potent immune activator by triggering Toll-like receptor (TLR) 7/8. Thus, we hypothesized that sustained TLR7 triggering induces chronic immune activation and thereby contributes to progressive immunodeficiency. We used the synthetic compound R848 or a mixture of uridine-rich HIV single-stranded (ss) RNA oligonucleotides--both are potent TLR7/8 agonists--to explore the effects of sustained TLR7 triggering on the murine lymphoid system. Sustained TLR7 triggering induced an immunopathology reminiscent of progressive lymphoid destruction in HIV disease; we observed lymphopenia, elevated proinflammatory cytokines, splenomegaly, contracted lymphoid subsets, and lymphoid microarchitecture alteration with reduced marginal zone B-lymphocytes. Upon exposure to inactivated vesiculo-stomatitis virus, antibody production was abolished, although splenic lymphocytes were activated and total IgG was elevated. Our data imply that HIV itself may directly contribute to immune activation and dysfunction by stimulating TLR7. Thus, manipulation of TLR7 signaling may be a potential strategy to reduce chronic hyper-immune activation and, thereby, disease progression in HIV infection.
Baenziger
Stefan
S
Division of Infectious Diseases and Hospital Epidemiology, University Hospital of Zurich, Zurich, Switzerland.
Heikenwalder
Mathias
M
Johansen
Pål
P
Schlaepfer
Erika
E
Hofer
Ursula
U
Miller
Regina C
RC
Diemand
Simone
S
Honda
Kenya
K
Kundig
Thomas M
TM
Aguzzi
Adriano
A
Speck
Roberto F
RF
D000163:Acquired Immunodeficiency Syndrome / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D000818:Animals; D000917:Antibody Formation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D005260:Female; D015497:HIV-1; D006801:Humans; D007093:Imidazoles / Q000276:immunology / Q000494:pharmacology*; D007074:Immunoglobulin G / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins / Q000819:agonists* / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D012367:RNA, Viral / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000819:agonists* / Q000235:genetics / Q000276:immunology*; D051200:Toll-Like Receptor 8 / Q000819:agonists / Q000235:genetics / Q000276:immunology
D007093:Imidazoles; D007074:Immunoglobulin G; D008562:Membrane Glycoproteins; D012367:RNA, Viral; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; C402365:resiquimod