Triggering TLR7 in mice induces immune activation and lymphoid system disruption, resembling HIV-mediated pathology

Stefan Baenziger, Mathias Heikenwalder, Pål Johansen, Erika Schlaepfer, Ursula Hofer, Regina C. Miller, Simone Diemand, Kenya Honda, Thomas M. Kundig, Adriano Aguzzi, Roberto F. Speck

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108 Citations (Scopus)

Abstract

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 oligonucleo-tides - 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 strategyto reduce chronic hyper-immune activation and, thereby, disease progression in HIV infection.

Original languageEnglish
Pages (from-to)377-388
Number of pages12
JournalBlood
Volume113
Issue number2
DOIs
Publication statusPublished - 2009 Jan 8

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Baenziger, S., Heikenwalder, M., Johansen, P., Schlaepfer, E., Hofer, U., Miller, R. C., Diemand, S., Honda, K., Kundig, T. M., Aguzzi, A., & Speck, R. F. (2009). Triggering TLR7 in mice induces immune activation and lymphoid system disruption, resembling HIV-mediated pathology. Blood, 113(2), 377-388. https://doi.org/10.1182/blood-2008-04-151712