Published online before print December 4, 2003

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(Journal of Leukocyte Biology. 2004;75:460-466.)
© 2004 by Society for Leukocyte Biology

The induction of Toll-like receptor tolerance enhances rather than suppresses HIV-1 gene expression in transgenic mice

André Báfica^*,1, Charles A. Scanga^*, Ozlem Equils and Alan Sher^*

^* Immunobiology Section, Laboratory of Parasitic Diseases, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland; and
Division of Pediatric Infectious Diseases, Steven Spielberg Pediatric Research Center, Burns and Allen Research Institute, Cedars-Sinai Medical Center, University of California School of Medicine, Los Angeles

¹ Correspondence: National Institutes of Health, 50 South Drive, MSC-8003, Building 50, Room 6146, Bethesda, MD 20982. E-mail: abafica{at}niaid.nih.gov

Microbial-induced proinflammatory pathways are thought to play a key role in the activation of human immunodeficiency virus type 1 (HIV-1) gene expression. The induction of Toll-like receptor (TLR) tolerance leads to a complex reprogramming in the pattern of inflammatory gene expression and down-modulates tumor necrosis factor (TNF-), interleukin (IL)-1, and IL-6 production. Using transgenic (Tg) mice that incorporate the entire HIV-1 genome, including the long-terminal repeat, we have previously demonstrated that a number of different TLR ligands induce HIV-1 gene expression in cultured splenocytes as well as purified antigen-presenting cell populations. Here, we have used this model to determine the effect of TLR-mediated tolerance as an approach to inhibiting microbial-induced viral gene expression in vivo. Unexpectedly, Tg splenocytes and macrophages, rendered tolerant in vitro to TLR2, TLR4, and TLR9 ligands as assessed by proinflammatory cytokine secretion and nuclear factor-B activation, showed enhanced HIV-1 p24 production. A similar enhancement was observed in splenocytes tolerized and then challenged with heterologous TLR ligands. Moreover, TLR2- and TLR4-homotolerized mice demonstrated significantly increased plasma p24 production in vivo despite lower levels of TNF-. Together, these results demonstrate that HIV-1 expression is enhanced in TLR-reprogrammed host cells, possibly reflecting a mechanism used by the virus to escape the effects of microbial-induced tolerance during natural infection in vivo.

Key Words: AIDS • bacterial • LPS • inflammation • TLR • HIV

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