Repeated lipopolysaccharide (LPS) exposure inhibits HIV replication in primary human macrophages.
Repetitive exposure of macrophages to microbial antigen is known to tolerize them to further stimulation and to inhibit proinflammatory cytokine release. Using transgenic (Tg) mice that incorporate the entire HIV-1 genome we have previously shown that toll like receptor (TLR)-2, -4, and -9 ligands induced tolerance as assessed by decreased proinflammatory cytokine secretion and nuclear factor-kappa beta activation. Yet, despite cytokine modulation, HIV-1 p24 production was enhanced in tolerized cells in vitro and in vivo. Since mice are not natural hosts for HIV infection, in the following report we examined whether TLR2 and TLR4 ligands induced tolerance in human monocytic cell lines stably expressing the HIV-long terminal repeat (LTR) luciferase construct (THP-LTR-Luc) as well as in primary macrophages that had been infected with HIV(BAL)in vitro. In THP-LTR-luc, TLR2 and TLR4 tolerization suppressed tumor necrosis factor (TNF)-alpha release and HIV-LTR transactivation. In HIV(BAL) infected macrophages, repeated LPS exposure inhibited HIV replication as assessed by decreased genetic expression and protein production of HIV-1 p24, although TNF-alpha release was not inhibited. These observations may have important clinical implications in understanding the role of macrophages as HIV reservoirs at anatomical sites where there is repeated exposure to microbial antigens.
Equils
Ozlem
O
Division of Pediatric Infectious Diseases, Ahmanson Department of Pediatrics, Steven Spielberg Pediatric Research Center, Burns and Allen Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. ozlem.equils@cshs.org
Salehi
Ken Khosrowdad
KK
Cornateanu
Randall
R
Cornataeanu
Randall
R
Lu
Daning
D
Singh
Sapna
S
Whittaker
Katherine
K
Baldwin
Gayle Cocita
GC
D001427:Bacterial Toxins / Q000494:pharmacology; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D016325:HIV Long Terminal Repeat / Q000235:genetics; D015497:HIV-1 / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000502:physiology / Q000821:virology; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology*; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects*
D001427:Bacterial Toxins; D022782:CCAAT-Enhancer-Binding Protein-beta; D008070:Lipopolysaccharides; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C025971:staphylococcal delta toxin; D008156:Luciferases