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Journal of Virology, August 2008, p. 7790-7798, Vol. 82, No. 16
0022-538X/08/$08.00+0     doi:10.1128/JVI.00362-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Human Immunodeficiency Virus Infection Alters Tumor Necrosis Factor Alpha Production via Toll-Like Receptor-Dependent Pathways in Alveolar Macrophages and U1 Cells{triangledown}

Marlynne Q. Nicol,1* Jean-Marie Mathys,2 Albertina Pereira,1 Kevin Ollington,1 Michael H. Ieong,1,3 and Paul R. Skolnik1

Center for HIV/AIDS Care and Research, Boston University School of Medicine, Boston, Massachusetts,1 Molecular and Clinical Genetics, Royal Prince Alfred Hospital and University of Sydney, Sydney, Australia,2 Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts3

Received 19 February 2008/ Accepted 27 May 2008

Human immunodeficiency virus (HIV)-positive persons are predisposed to pulmonary infections, even after receiving effective highly active antiretroviral therapy. The reasons for this are unclear but may involve changes in innate immune function. HIV type 1 infection of macrophages impairs effector functions, including cytokine production. We observed decreased constitutive tumor necrosis factor alpha (TNF-{alpha}) concentrations and increased soluble tumor necrosis factor receptor type II (sTNFRII) in bronchoalveolar lavage fluid samples from HIV-positive subjects compared to healthy controls. Moreover, net proinflammatory TNF-{alpha} activity, as measured by the TNF-{alpha}/sTNFRII ratio, decreased as HIV-related disease progressed, as manifested by decreasing CD4 cell count and increasing HIV RNA (viral load). Since TNF-{alpha} is an important component of the innate immune system and is produced upon activation of Toll-like receptor (TLR) pathways, we hypothesized that the mechanism associated with deficient TNF-{alpha} production in the lung involved altered TLR expression or a deficit in the TLR signaling cascade. We found decreased Toll-like receptor 1 (TLR1) and TLR4 surface expression in HIV-infected U1 monocytic cells compared to the uninfected parental U937 cell line and decreased TLR message in alveolar macrophages (AMs) from HIV-positive subjects. In addition, stimulation with TLR1/2 ligand (Pam3Cys) or TLR4 ligand (lipopolysaccharide) resulted in decreased intracellular phosphorylated extracellular signal-regulated kinase and subsequent decreased transcription and expression of TNF-{alpha} in U1 cells compared to U937 cells. AMs from HIV-positive subjects also showed decreased TNF-{alpha} production in response to these TLR2 and TLR4 ligands. We postulate that HIV infection alters expression of TLRs with subsequent changes in mitogen-activated protein kinase signaling and cytokine production that ultimately leads to deficiencies of innate immune responses that predispose HIV-positive subjects to infection.

* Corresponding author. Mailing address: Center for HIV/AIDS Care and Research, Department of Medicine, Evans Biomedical Research Center, Boston University Medical Center, 650 Albany Street, EBRC 640, Boston, MA 02118-2393. Phone: (617) 638-8052. Fax: (617) 414-5218. E-mail: mnicol{at}bu.edu

{triangledown} Published ahead of print on 4 June 2008.

Journal of Virology, August 2008, p. 7790-7798, Vol. 82, No. 16
0022-538X/08/$08.00+0     doi:10.1128/JVI.00362-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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