title: The induction of Toll-like receptor tolerance enhances rather than suppresses HIV-1 gene expression in transgenic mice.
abstract: 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 alpha (TNF-alpha), 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-kappaB 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-alpha. 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.
authors.affiliation: Immunobiology Section, Laboratory of Parasitic Diseases, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20982, USA. abafica@niaid.nih.gov
authors.forename: André
authors.initials: A
authors.lastname: Báfica
authors.forename: Charles A
authors.initials: CA
authors.lastname: Scanga
authors.forename: Ozlem
authors.initials: O
authors.lastname: Equils
authors.forename: Alan
authors.initials: A
authors.lastname: Sher
mesh_terms: D000818:Animals; D003545:Cysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis; D004361:Drug Tolerance; D005786:Gene Expression Regulation / Q000276:immunology; D015967:Gene Expression Regulation, Viral; D016655:HIV Core Protein p24 / Q000097:blood; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics*; D007108:Immune Tolerance; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008074:Lipoproteins / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D011956:Receptors, Cell Surface / Q000276:immunology*; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
chemical_list: D016207:Cytokines; D016655:HIV Core Protein p24; D008070:Lipopolysaccharides; D008074:Lipoproteins; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; C069172:2,3-bis(palmitoyloxy)-2-propyl-1-palmitoylcysteine; D003545:Cysteine