Review
The role of collagen deposition in depleting CD4+ T cells and limiting reconstitution in HIV-1 and SIV infections through damage to the secondary lymphoid organ niche

https://doi.org/10.1016/j.smim.2008.04.002Get rights and content

Abstract

The hallmark of HIV/SIV infections is the progressive depletion of CD4+ T cells that ultimately renders the host incapable of defending against AIDS defining opportunistic infections and malignancies. Although many potential mechanisms have been proposed to explain CD4+ T cell loss, we review here the growing evidence that fibrotic ‘scarring’ and consequent damage to the lymphatic tissue niche contributes to CD4+ T cell decline and limits CD4+ T cell re-population with retroviral therapy.

Introduction

As a consequence of CD4+ T cell depletion, individuals infected with the human immunodeficiency virus (HIV), the causative agent of the acquired immune deficiency syndrome (AIDS) eventually succumb to opportunistic infections and malignancies if they do not receive antiretroviral therapy (ART). The World Health Organization estimates 25 million people have already died from AIDS since it was first recognized 25 years ago and that more than 32 million people are currently living with HIV-1 infection [1].

Inhibiting viral replication with ART and reconstituting immunity, measured by increases in peripheral blood CD4+ T cells has had great impact on this terrible morbidity and mortality of HIV-1 infection. Patients are living longer-healthier lives and mortality in the treated population of HIV+ patients has significantly declined. However up to 20% of treated individuals receive no clinical benefit because, despite suppression of replicating virus in plasma, immune reconstitution is limited or absent [2], [3]. Further, even among patients with significant increases in peripheral blood CD4+ T cells, few reconstitute to normal levels. While the data are clear that significant increases may be sufficient to avert opportunistic infections, there is increasing recognition that these individuals may still be at risk for complications of a subtler kind of immune suppression. Recent data indeed suggest that rates of malignancy appear to be increasing in the ARV-treated HIV+ population, even among those with significant reconstitution [4], [5], [6], [7], [8].

It is not clear why immune reconstitution is robust with ART in some individuals and not in others. One potential explanation for the variable immune reconstitution with ART we review here is inflammation induced structural damage to the lymphatic tissue niche that normally maintains CD4+ T cell populations. We propose that this damaged niche is an important mechanism both in limiting reconstitution and in CD4+ T cell loss.

Section snippets

Depletion of CD4+ T cells in lymphatic tissues and the damaged niche hypothesis

CD4+ T cell depletion in peripheral blood and secondary lymphatic tissues of LN and GALT where most (98%) of CD4+ T cells reside is the hallmark of HIV infection. Severe depletion occurs within 14 days of HIV acquisition (i.e. during the period of seroconversion) in the lamina propria of GALT (the effector site) and by the time the individual progresses to the chronic stage of disease >50% of CD4+ T cells in LN are lost [9], [10], [11], [12], [13], [14], [15].

Multiple mechanisms responsible for

Transmission and establishment of the lymphatic tissue reservoir

HIV-1 is primarily transmitted across mucosal surfaces, globally now most commonly by intravaginal exposure [1]. More than 90% of the first productively infected cells are a recently activated but ostensibly immunophenotypically ‘resting’ CD4+ T cells [47], [48], and expansion of infection from small founder populations of these infected cells ‘broadcasts’ virus and infected cells, first to the draining lymph nodes and then systemically, in sufficient numbers to establish and maintain virus

How fibrosis in the TZ niche might limit CD4+ T cell populations

There are at least four potential ways that collagen deposition within secondary lymphatic tissues might impact CD4+ T cell population sizes before and during ART. First, collagen deposition and lymphatic tissue scarring could physically limit the space or ‘niche’ that T cells could occupy. Progressive collagen deposition in both HIV and SIV infections can account for up to one-third of the area of the T cell zone [20], [65], [66], [67], thus placing a physical limitation on the space in which

Conclusion

Lymphatic tissues are the primary site of HIV replication and as a result sustain significant architectural damage. There are significant functional sequelae with reduced numbers of CD4+ T cells, particularly naïve CD4+ T cells and likely impaired antigen response from changes in trafficking. These changes are progressive and do not appear to reverse with antiretroviral therapy alone. It is possible that therapies targeting TGFβ might inhibit or reverse this process and thus, aid efforts at

Acknowledgements

The authors would like to thank Tim Leonard and Jacob Barthold for their assistance in figure preparation.

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    This work was supported by National Institutes of Health grants R01 AI48484 and AI056997 to A.T.H., T32 AI07421 to J.D.E., and Public Health P130-CA79458-01, 1RO1DE12934-01, MO1 RR00400, 2UO1 AI041535, RO1 AI54232-01A2, and R37 AI 28246. This project has also been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.

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