CD4+ T Cell Depletion during all Stages of HIV Disease Occurs Predominantly in the Gastrointestinal Tract

TLDR

The mechanisms driving CD4+ T cell depletion in HIV infection remain poorly understood. The study aims to compare lymphoid tissues and peripheral blood to clarify HIV‑associated disease pathogenesis. Researchers examined HIV‑induced activation and depletion of CD4+ and CD8+ T cell subsets in blood, the gastrointestinal tract, and lymph nodes, measuring HIV‑specific T cell frequencies and lymph node collagen deposition to assess chronic inflammation. They found that the gastrointestinal tract exhibits the greatest CD4+ T cell loss at all disease stages, predominantly affecting CCR5+ cells, while lymph node immune activation leads to abnormal effector T cell accumulation, collagen deposition, and a mismatch between HIV‑specific and total effector T cells, highlighting CCR5+ depletion and disrupted homeostasis as key mechanisms.

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.