Cumulative mechanisms of lymphoid tissue fibrosis and T cell depletion in HIV-1 and SIV infections
Ming Zeng, … , John V. Carlis, Ashley T. Haase
Ming Zeng, … , John V. Carlis, Ashley T. Haase
Published February 14, 2011
Citation Information: J Clin Invest. 2011;121(3):998-1008. https://doi.org/10.1172/JCI45157.
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Research Article Virology

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

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.

Authors

Ming Zeng, Anthony J. Smith, Stephen W. Wietgrefe, Peter J. Southern, Timothy W. Schacker, Cavan S. Reilly, Jacob D. Estes, Gregory F. Burton, Guido Silvestri, Jeffrey D. Lifson, John V. Carlis, Ashley T. Haase

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Figure 5

Loss of FRCs is associated with loss of naive T cells within LTs.

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Loss of FRCs is associated with loss of naive T cells within LTs. (A) Co...
(A) Confocal images of LN sections from RMs at different time points after SIV infection immunofluorescently double stained for CD45RA (green) and CD3 (red), showing gradual loss of CD45RA+CD3+ naive T cells within LTs during SIV infection (total n = 38; n = 9 for uninfected RMs, n = 5 for 7-dpi RMs, n = 5 for 14-dpi RMs, n = 5 for 30-dpi RMs, n = 4 for 90-dpi RMs, n = 5 for 180-dpi RMs, and n = 5 for 300-dpi RMs). Scale bar: 30 μm. (B) Quantification of the number of apoptotic naive T cells (TUNEL+CD45RA+CD3+) and the number of naive T cells (CD45RA+CD3+), showing significant inverse association (total n = 38, P = 0.0001). The time point “300 dpi” represents the mean measurement of 5 animals, which were infected for 222 days, 280 days, 294 days, 462 days, and 560 days, respectively. (C) QIA of the percentage of area staining positive for desmin and the percentage of area staining positive for IL-7, showing significant association between the quantity of IL-7 and the quantity of the FRC network (total n = 38, P < 0.0001). (D) QIA of the percentage of area staining positive for IL-7 and the number of CD45RA+CD3+ naive T cells within LTs, showing the kinetics of IL-7 and the kinetics of naive T cell number. Error bars represent SD. (E) QIA of the percentage of area staining positive for IL-7 and the number of CD45RA+CD3+ naive T cells for each animal, showing that loss of naive T cells is associated with loss of IL-7 production (total n = 38, P = 0.0004).