HIV-1 RNA Dysregulates the Natural TLR Response to Subclinical Endotoxemia in Kenyan Female Sex-Workers

• Published in: PloS one Vol. 4; no. 5; p. e5644
• Main Authors: Lester, Richard T., Yao, Xiao-Dan, Ball, T. Blake, McKinnon, Lyle R., Omange, Were R., Kaul, Rupert, Wachihi, Charles, Jaoko, Walter, Rosenthal, Kenneth L., Plummer, Francis A.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 21.05.2009; Public Library of Science (PLoS)
• Subjects: Acquired immune deficiency syndrome; Activation; Adult; AIDS; Antiretroviral drugs; Blood; Cell culture; Chronic conditions; Chronic infection; Cytokines; Cytokines - metabolism; Dementia; Development and progression; Drug therapy; Endotoxemia; Endotoxemia - blood; Endotoxemia - immunology; Endotoxins; Female; Gene expression; Gene Expression Regulation; HIV; HIV (Viruses); HIV infection; HIV Infections - blood; HIV-1 - immunology; Human immunodeficiency virus; Human immunodeficiency virus 1; Humans; Immune response; Immune system; Immune Tolerance - immunology; Immunological tolerance; Immunology; Immunology/Cellular Microbiology and Pathogenesis; Immunology/Immune Response; Immunology/Immunity to Infections; Immunology/Immunomodulation; Immunology/Innate Immunity; Immunology/Leukocyte Activation; Infections; Infectious Diseases; Infectious Diseases/Bacterial Infections; Infectious Diseases/HIV Infection and AIDS; Infectious Diseases/Viral Infections; Inflammation; Kenya; Laboratories; Leukocytes (mononuclear); Ligands; Lipopolysaccharides; Lipopolysaccharides - blood; Lymphocytes; Lymphocytes - metabolism; Middle Aged; Pathogenesis; Peripheral blood mononuclear cells; Plasma; Plasmas (physics); Polymerase chain reaction; Proteins; Public health; Ribonucleic acid; RNA; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA, Viral - immunology; Sepsis; Sex; Sex Work; Sexually transmitted diseases; Signal Transduction; STD; Stimulation; Studies; T cell receptors; TLR4 protein; Toll-Like Receptor 4 - genetics; Toll-Like Receptor 4 - metabolism; Toll-like receptors; Toll-Like Receptors - immunology; Trends; Tumor necrosis factor-α; Workers; Canada; Manitoba Canada
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0005644

Subclinical endotoxemia has been reported in HIV-1 infected persons and may drive systemic immune activation and pathogenesis. Proinflammatory responsiveness to endotoxin (LPS) is mediated by Toll-like receptor 4 (TLR4). We therefore examined the association between plasma LPS levels, HIV RNA, and TLR4 expression and cytokine responses in the blood of HIV infected and uninfected participants in a cohort of female sex-workers in Kenya. Ex vivo plasma and peripheral blood mononuclear cells (PBMC) were assessed for LPS and TLR mRNA, respectively. The effects of HIV single stranded RNA, a TLR8 ligand, on TLR4 and LPS signaling were further assessed in short term PBMC culture. Both HIV uninfected and infected subjects frequently had low detectable LPS levels in their plasmas. Significantly increased LPS levels were associated with chronic HIV-1 infection, both treated and untreated, but not with other acute or semi-chronic conditions reported. In HIV-uninfected subjects, TLR4 mRNA expression levels correlated inversely with plasma LPS levels, suggesting chronic endotoxin 'tolerance' in vivo. A similar effect of reduced TLR4 mRNA was seen in short term PBMC culture after stimulation with LPS. Interestingly, the apparent in vivo tolerance effect was diminished in subjects with HIV infection. Additionally, pre-stimulation of PBMC with LPS lead to proinflammatory (TNF-alpha) tolerance to subsequent LPS stimulation; however, pre-treatment of PBMC with HIV single-stranded RNA40, could enhance TLR4-mediated LPS responsiveness in vitro. Thus, dysregulation of endotoxin tolerance by HIV-1 RNA may exacerbate HIV chronic immune activation and pathogenesis.