Gut Epithelial Barrier Dysfunction and Innate Immune Activation Predict Mortality in Treated HIV Infection

• Published in: The Journal of infectious diseases Vol. 210; no. 8; pp. 1228 - 1238
• Main Authors: Hunt, Peter W., Sinclair, Elizabeth, Rodriguez, Benigno, Shive, Carey, Clagett, Brian, Funderburg, Nicholas, Robinson, Janet, Huang, Yong, Epling, Lorrie, Martin, Jeffrey N., Deeks, Steven G., Meinert, Curtis L., Van Natta, Mark L., Jabs, Douglas A., Lederman, Michael M.
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 15.10.2014
• Subjects: Adult; AIDS; Antiretrovirals; Biomarkers; Blood Coagulation; Case-Control Studies; Cytomegalovirus; Female; Hepacivirus; HIV; HIV infections; HIV Infections - drug therapy; HIV Infections - immunology; HIV Infections - mortality; HIV/AIDS; Human immunodeficiency virus; Humans; Immunity, Innate - physiology; Inflammation - metabolism; Intestinal Mucosa - physiopathology; Lymphocyte Activation; Major and Brief Reports; Male; Middle Aged; Mortality rates; Solubility; T lymphocytes; T-Lymphocytes - physiology; sCD14; antiretroviral therapy; immune activation; D-dimer; IL-6; zonulin-1; T-cell activation; gut epithelial cell barrier; HIV; HLA-DR; cytomegalovirus; CD28; hsCRP; mortality; CD38; CD57; intestinal fatty acid binding protein (I-FABP)
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1093/infdis/jiu238

Background. While inflammation predicts mortality in treated human immunodeficiency virus (HIV) infection, the prognostic significance of gut barrier dysfunction and phenotypic T-cell markers remains unclear. Methods. We assessed immunologic predictors of mortality in a case-control study within the Longitudinal Study of the Ocular Complications of AIDS (LSOCA), using conditional logistic regression. Sixty-four case patients who died within 12 months of treatment-mediated viral suppression were each matched to 2 control individuals (total number of controls, 128) by duration of antiretroviral therapy-mediated viral suppression, nadir CD4⁺ T-cell count, age, sex, and prior cytomegalovirus (CMV) retinitis. A similar secondary analysis was conducted in the SCOPE cohort, which had participants with less advanced immunodeficiency. Results. Plasma gut epithelial barrier integrity markers (intestinal fatty acid binding protein and zonulin-1 levels), soluble CD14 level, kynurenine/tryptophan ratio, soluble tumor necrosis factor receptor 1 level, high-sensitivity C-reactive protein level, and D-dimer level all strongly predicted mortality, even after adjustment for proximal CD4⁺ T-cell count (all P ≤001). A higher percentage of CD38⁺HLA-DR⁺ cells in the CD8⁺ T-cell population was a predictor of mortality before (P = .031) but not after (P = .10) adjustment for proximal CD4⁺ T-cell count. Frequencies of senescent (defined as CD28⁻CD57⁺ cells), exhausted (defined as PD1⁺ cells), naive, and CMV-specific T cells did not predict mortality. Conclusions. Gut epithelial barrier dysfunction, innate immune activation, inflammation, and coagulation—but not T-cell activation, senescence, and exhaustion—independently predict mortality in individuals with treated HIV infection with a history of AIDS and are viable targets for interventions.