Human immunodeficiency virus type 1 protease inhibitors block toll-like receptor 2 (TLR2)- and TLR4-Induced NF-kappaB activation.

Abstract

Coinfections with opportunistic and pathogenic bacteria induce human immunodeficiency virus (HIV) replication through microbial antigen activation of NF-kappaB. Here, we assessed whether HIV type 1 protease inhibitors (PI) block microbial antigen activation of NF-kappaB. Human microvessel endothelial cells were transiently transfected with either endothelial cell-leukocyte adhesion molecule NF-kappaB luciferase or interleukin 6 (IL-6) promoter luciferase constructs by using FuGENE 6, and they were treated with PI (nelfinavir, ritonavir, or saquinavir) prior to stimulation with the Toll-like receptor 4 (TLR4) and TLR2 ligands, with lipopolysaccharide (LPS), soluble Mycobacterium tuberculosis factor, or Staphylococcus epidermidis phenol-soluble modulin, respectively, or with tumor necrosis factor alpha (TNF-alpha). Luciferase activity was measured by using a Promega luciferase kit. TNF-alpha release from the supernatant was measured by enzyme-linked immunosorbent assay. Cell death was assessed by lactate dehydrogenase assay. We observed that PI pretreatment blocked the TLR2- and TLR4- as well as the TNF-alpha-mediated NF-kappaB activation, in a dose-dependent manner. PI pretreatment also blocked the LPS-induced IL-6 promoter transactivation and TNF-alpha secretion. These data suggest that PI block HIV replication not only by inhibiting the HIV protease but also by blocking the TLR- and TNF-alpha-mediated NF-kappaB activation and proinflammatory cytokine production. These findings may help explain the immunomodulatory effects of PI, and they suggest an advantage for PI-containing drug regimens in the treatment of HIV-infected patients who are coinfected with opportunistic and pathogenic bacteria.

• Authors: Ozlem Equils, Alan Shapiro, Zeynep Madak, Chunren Liu, Daning Lu
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 48 Issue 10 Pg. 3905-11 (Oct 2004) ISSN: 0066-4804 [Print] United States
• PMID: 15388451 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• HIV Protease Inhibitors
• Interleukin-6
• Lipopolysaccharides
• Membrane Glycoproteins
• NF-kappa B
• Receptors, Cell Surface
• TLR2 protein, human
• TLR4 protein, human
• Toll-Like Receptor 2
• Toll-Like Receptor 4
• Toll-Like Receptors
• Tumor Necrosis Factor-alpha
• L-Lactate Dehydrogenase
• Luciferases

Topics

• Dose-Response Relationship, Drug
• Endothelial Cells (drug effects, enzymology)
• Enzyme-Linked Immunosorbent Assay
• HIV Protease Inhibitors (pharmacology)
• HIV-1 (enzymology)
• Humans
• Interleukin-6 (biosynthesis, genetics)
• L-Lactate Dehydrogenase (genetics, metabolism)
• Lipopolysaccharides (pharmacology)
• Luciferases (biosynthesis, genetics)
• Membrane Glycoproteins (antagonists & inhibitors, genetics)
• NF-kappa B (drug effects)
• Receptors, Cell Surface (antagonists & inhibitors, genetics)
• Toll-Like Receptor 2
• Toll-Like Receptor 4
• Toll-Like Receptors
• Tumor Necrosis Factor-alpha (analysis, metabolism)