title: Defective response to Toll-like receptor 3 and 4 ligands by activated monocytes in chronic hepatitis C virus infection.
abstract: Toll-like receptors (TLR) have a critical role in innate immunity against pathogens. We investigated the cytokine response to TLR stimulation in peripheral blood cells of subjects infected with hepatitis C virus (HCV) and/or human immunodeficiency virus (HIV) in the Women Interagency HIV Study (WIHS) cohort. Interleukin (IL)-6 in response to TLR3 and TLR4 ligands such as polyinosinic-polycytidylic acid and lipopolysaccharide was significantly compromised in HCV-infected women. High spontaneous secretion of IL-6 suggested pre-existing cell activation as a factor mediating reduced responses to TLR3 and TLR4 stimulation. To a lesser extent, tumour necrosis factor-alpha and IL-1beta responses to TLR stimulation were also compromised. Monocytes, but not B cells or NK cells, were identified as the cell population spontaneously secreting cytokines and also as the cells responding to TLR stimulation. These results highlight a functional defect in antigen-presenting cells of women with HCV infection or co-infection. In women with existing HIV co-infection, decreased cytokine function of antigen-presenting cells suggests another mechanism contributing to immune dysfunction in addition to the HIV-associated CD4 defect.
authors.affiliation: Maternal, Child and Adolescent Center for Infectious Diseases and Virology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA. villacre@usc.edu
authors.forename: M C
authors.initials: MC
authors.lastname: Villacres
authors.forename: O
authors.initials: O
authors.lastname: Literat
authors.forename: M
authors.initials: M
authors.lastname: DeGiacomo
authors.forename: W
authors.initials: W
authors.lastname: Du
authors.forename: T
authors.initials: T
authors.lastname: Frederick
authors.forename: A
authors.initials: A
authors.lastname: Kovacs
mesh_terms: D000938:Antigen-Presenting Cells; D003430:Cross-Sectional Studies; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D015497:HIV-1 / Q000276:immunology; D016174:Hepacivirus / Q000276:immunology* / Q000502:physiology; D019698:Hepatitis C, Chronic / Q000150:complications / Q000276:immunology / Q000473:pathology* / Q000821:virology; D006801:Humans; D015850:Interleukin-6 / Q000276:immunology; D008024:Ligands; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism* / Q000821:virology; D051196:Toll-Like Receptor 3 / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D016207:Cytokines; D015850:Interleukin-6; D008024:Ligands; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4