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Antimicrobial Agents and Chemotherapy, October 2004, p. 3905-3911, Vol. 48, No. 10
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.10.3905-3911.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Human Immunodeficiency Virus Type 1 Protease Inhibitors Block Toll-Like Receptor 2 (TLR2)- and TLR4-Induced NF-{kappa}B Activation

Ozlem Equils,1* Alan Shapiro,2,{dagger} Zeynep Madak,1,{ddagger} Chunren Liu,1 and Daning Lu1

Ahmanson Department of Pediatrics, Division of Pediatric Infectious Diseases, Steven Spielberg Pediatric Research Center, Cedars-Sinai Medical Center, and David Geffen School of Medicine at UCLA,1 Division of Pediatric Infectious Diseases, Mattel Children's Hospital at UCLA, and Department of Molecular & Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California2

Received 23 March 2004/ Returned for modification 25 May 2004/ Accepted 24 June 2004

Coinfections with opportunistic and pathogenic bacteria induce human immunodeficiency virus (HIV) replication through microbial antigen activation of NF-{kappa}B. Here, we assessed whether HIV type 1 protease inhibitors (PI) block microbial antigen activation of NF-{kappa}B. Human microvessel endothelial cells were transiently transfected with either endothelial cell-leukocyte adhesion molecule NF-{kappa}B 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-{kappa}B 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-{kappa}B 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.

* Corresponding author. Mailing address: Department of Pediatrics, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Room 4220, Los Angeles, CA 90048. Phone: (310) 423-4471. Fax: (310) 423-8284. E-mail: ozlem.equils{at}cshs.org.

{dagger} Present address: Division of Pediatric Drug Development, Office of Counter-Terrorism and Pediatric Drug Development, Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, MD 20855.

{ddagger} Present address: University of California, San Francisco, San Francisco, CA 94107.

Antimicrobial Agents and Chemotherapy, October 2004, p. 3905-3911, Vol. 48, No. 10
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.10.3905-3911.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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