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The induction of Toll‐like receptor tolerance enhances rather than suppresses HIV‐1 gene expression in transgenic mice
Author(s) -
Báfica André,
Scanga Charles A.,
Equils Ozlem,
Sher Alan
Publication year - 2004
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.0803388
Subject(s) - biology , proinflammatory cytokine , tlr4 , tlr2 , tlr9 , tumor necrosis factor alpha , tlr7 , cytokine , transgene , microbiology and biotechnology , toll like receptor , gene expression , immune system , immunology , signal transduction , innate immune system , inflammation , gene , dna methylation , biochemistry
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 α (TNF‐α), 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‐κB 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‐α. 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.