Cumulative mechanisms of lymphoid tissue fibrosis and T cell depletion in HIV-1 and SIV infections

J Clin Invest. 2011 Mar;121(3):998-1008. doi: 10.1172/JCI45157.

Abstract

The hallmark of HIV-1 and SIV infections is CD4(+) T cell depletion. Both direct cell killing and indirect mechanisms related to immune activation have been suggested to cause the depletion of T cells. We have now identified a mechanism by which immune activation-induced fibrosis of lymphoid tissues leads to depletion of naive T cells in HIV-1 infected patients and SIV-infected rhesus macaques. The T regulatory cell response to immune activation increased procollagen production and subsequent deposition as fibrils via the TGF-β1 signaling pathway and chitinase 3-like-1 activity in fibroblasts in lymphoid tissues from patients infected with HIV-1. Collagen deposition restricted T cell access to the survival factor IL-7 on the fibroblastic reticular cell (FRC) network, resulting in apoptosis and depletion of T cells, which, in turn, removed a major source of lymphotoxin-β, a survival factor for FRCs during SIV infection in rhesus macaques. The resulting loss of FRCs and the loss of IL-7 produced by FRCs may thus perpetuate a vicious cycle of depletion of T cells and the FRC network. Because this process is cumulative, early treatment and antifibrotic therapies may offer approaches to moderate T cell depletion and improve immune reconstitution during HIV-1 infection.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipokines
  • Animals
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / virology
  • Chitinase-3-Like Protein 1
  • Fibroblasts / cytology
  • Glycoproteins / metabolism
  • HIV Infections / immunology*
  • HIV-1 / genetics*
  • Humans
  • Interleukin-7 / metabolism
  • Lectins / metabolism
  • Lymphocytes / cytology
  • Macaca mulatta
  • Retroviridae Infections / immunology*
  • Signal Transduction
  • Simian Immunodeficiency Virus / metabolism*
  • T-Lymphocytes / cytology*
  • Transforming Growth Factor beta1 / metabolism

Substances

  • Adipokines
  • CHI3L1 protein, human
  • Chitinase-3-Like Protein 1
  • Glycoproteins
  • Interleukin-7
  • Lectins
  • Transforming Growth Factor beta1