CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract

Jason M. Brenchley, Timothy W Schacker, Laura E. Ruff, David A. Price, Jodie H. Taylor, Gregory J Beilman, Phuong L. Nguyen, Alexander Khoruts, Matthew Larson, Ashley T Haase, Daniel C. Douek

Research output: Contribution to journalArticle

1294 Scopus citations

Abstract

The mechanisms underlying CD4+ T cell depletion in human immunodeficiency virus (HIV) infection are not well understood. Comparative studies of lymphoid tissues, where the vast majority of T cells reside, and peripheral blood can potentially illuminate the pathogenesis of HIV-associated disease. Here, we studied the effect of HIV infection on the activation and depletion of defined subsets of CD4+ and CD8+ T cells in the blood, gastrointestinal (GI) tract, and lymph node (LN). We also measured HIV-specific T cell frequencies in LNs and blood, and LN collagen deposition to define architectural changes associated with chronic inflammation. The major findings to emerge are the following: the GI tract has the most substantial CD4+ T cell depletion at all stages of HIV disease; this depletion occurs preferentially within CCR5+ CD4+ T cells; HIV-associated immune activation results in abnormal accumulation of effector-type T cells within LNs; HIV-specific T cells in LNs do not account for all effector T cells; and T cell activation in LNs is associated with abnormal collagen deposition. Taken together, these findings define the nature and extent of CD4+ T cell depletion in lymphoid tissue and point to mechanisms of profound depletion of specific T cell subsets related to elimination of CCR5+ CD4+ T cell targets and disruption of T cell homeostasis that accompanies chronic immune activation.

Original languageEnglish (US)
Pages (from-to)749-759
Number of pages11
JournalJournal of Experimental Medicine
Volume200
Issue number6
DOIs
StatePublished - Sep 20 2004

Keywords

  • CD4 T cell depletion
  • Gastrointestinal tract
  • HIV pathogenesis
  • HIV-specific T cells
  • Lymph nodes

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