The Journal of Experimental Medicine
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Published online 13 September 2004 doi:10.1084/jem.20040874
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 6, 749-759
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CD4+ T Cell Depletion during all Stages of HIV Disease Occurs Predominantly in the Gastrointestinal Tract

Jason M. Brenchley1, Timothy W. Schacker2, Laura E. Ruff1, David A. Price1, Jodie H. Taylor3, Gregory J. Beilman3, Phuong L. Nguyen5, Alexander Khoruts2, Matthew Larson2, Ashley T. Haase4, and Daniel C. Douek1

1 Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD 20892
2 Department of Medicine, Division of Surgical Critical Care
3 Department of Surgery, Division of Surgical Critical Care
4 Department of Microbiology, University of Minnesota, Minneapolis, MN 55455
5 Division of Hematopathology, Mayo Clinic, Rochester, MN 55905

Address correspondence to D.C. Douek, Human Immunology Section, Vaccine Research Center, National Institutes of Health, 40 Convent Dr., Room 3509, Bethesda, MD 20892. Phone: (301) 594-8484; Fax: (301) 480-2565; email: ddouek{at}nih.gov

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.

Key Words: HIV pathogenesis • CD4+ T cell depletion • lymph nodes • gastrointestinal tract • HIV-specific T cells

Abbreviations used in this paper: GI, gastrointestinal; SIV, simian immunodeficiency; TEM cell, effector–memory T cell.


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