Gut epithelial barrier dysfunction and innate immune activation predict mortality in treated HIV infection

Peter W. Hunt, Elizabeth Sinclair, Benigno Rodriguez, Carey Shive, Brian Clagett, Nicholas Funderburg, Janet Robinson, Yong Huang, Lorrie Epling, Jeffrey N. Martin, Steven G. Deeks, Curtis L. Meinert, Mark L. Van Natta, Douglas A. Jabs, Michael M. Lederman

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1228-1238
Number of pages11
JournalJournal of Infectious Diseases
Volume210
Issue number8
DOIs
StatePublished - Oct 15 2014

Keywords

  • Antiretroviral therapy
  • CD28
  • CD38
  • CD57
  • Cytomegalovirus
  • D-dimer
  • Gut epithelial cell barrier
  • HIV
  • HLA-DR
  • IL-6
  • Immune activation
  • Intestinal fatty acid binding protein (I-FABP)
  • Mortality
  • T-cell activation
  • Zonulin-1
  • hsCRP
  • sCD14

ASJC Scopus subject areas

  • Immunology and Allergy
  • Infectious Diseases

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