CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract.
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.
Brenchley
Jason M
JM
Human Immunology Section, Vaccine Research Center, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, 40 Convent Dr., Room 3509, Bethesda, MD 20892, USA.
Schacker
Timothy W
TW
Ruff
Laura E
LE
Price
David A
DA
Taylor
Jodie H
JH
Beilman
Gregory J
GJ
Nguyen
Phuong L
PL
Khoruts
Alexander
A
Larson
Matthew
M
Haase
Ashley T
AT
Douek
Daniel C
DC
D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D003094:Collagen / Q000378:metabolism; D004064:Digestive System / Q000276:immunology* / Q000821:virology; D015658:HIV Infections / Q000209:etiology / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation; D019713:Receptors, CCR5 / Q000032:analysis
D019713:Receptors, CCR5; D003094:Collagen