Review
Reconstitution of CD4+ T lymphocytes in HIV-infected individuals following antiretroviral therapy

https://doi.org/10.1016/S0952-7915(00)00245-4Get rights and content

Abstract

Immune reconstitution during antiretroviral therapy has recently been shown to depend upon multiple factors at work in T cell homeostasis, amongst which the reduction of thymus dysfunction and of immune hyperactivation are instrumental. The optimism that has been raised by the restoration of hosts’ defenses against opportunistic pathogens is, however, balanced by the poor immunity restored against HIV; thus, innovative immune interventions are required.

Introduction

Antiretroviral drug regimens combining inhibitors of the HIV reverse transcriptase and protease — the so-called ‘highly active antiretroviral therapy’ (HAART) — opened a new era in 1995 by inducing major reductions in viral load and increases in CD4+ T cell numbers. Since the first reports of immune restoration in 1997 [1], many mechanisms have been proposed to account for the increased T cell numbers. In addition to the recirculation of sequestered memory T cells, re-expansion of naı̈ve CD4+ T cells and rediversification of the CD4+ T cell repertoires, thymus cell-production and peripheral homeostasis have been shown to play central roles. These findings illustrate the plasticity of the lymphoid compartment even after the severe alterations induced by this virus. The limitation that has been found in the restoration of HIV-specific immunity also illustrates the tight equilibrium existing between virus exposure and numbers of specific CD4+ T cells.

We will focus this review on research during the past two years into the major mechanisms and limits of the restoration of the CD4+ T cell compartment.

Section snippets

The kinetics of CD4+ T cell reconstitution following HAART: a two-phase process

The rapid increase of CD4+ T cell counts observed during the first two months of antiretroviral treatment, concurrently with the reduction in plasma virus load, had been proposed in the initial descriptions of immune reconstitution to reflect a recirculation of T cells from lymphoid tissues 1., 2., 3.. Various studies performed on peripheral blood cells and on lymph nodes confirmed this redistribution hypothesis 4., 5., 6., 7., 8.. Recovery can be triggered at any stage of the CD4+ cell

Memory and naı̈ve CD4+ T cell numbers, thymus function and peripheral homeostasis following HAART

The early increase of CD4+ T cell numbers following HAART comprises activated memory CD45RO+ T cells 1., 2., 3.. Such cells do not incorporate proliferation markers such as propidium iodide [1] or Ki67; indeed, the proportions of CD4+Ki67+ T cells even decrease during that early period 5., 6., 8.. These findings support the hypothesis that early reconstitution does not reflect memory T cell proliferation but rather the release into the blood circulation, when virus replication is controlled, of

The correction of abnormal immune activation that follows HAART helps immune reconstitution

A rapid and remarkable reduction in the cell surface expression of various T cell activation markers on CD4+ T cells following HAART has been shown to occur in peripheral blood 1., 3., 9., 10. and in the tissues 5., 6., 7., 28., in parallel with the control of virus replication. Similarly, a reduction in Fas/FasL cell surface expression and in plasma levels of inflammatory cytokines TNF-α and IL-6 was also observed 3., 29.. Both phenomena help to reduce the abnormal rate of cell death observed

The restoration of host defenses following HAART: successes and limits

CD4+ T cell responses against cytomegalovirus (CMV) and Mycobacterium tuberculosis are rapidly restored after three months of HAART in AIDS patients 1., 3., 20., 31., 32., 33., concurrently with increased memory CD4+ cell numbers and normalization of the inflammatory syndrome. Recently developed flow-cytometry assays of intra-cellular production of cytokines have helped to demonstrate the net increases in frequencies of CMV-specific CD4+ T cells after introduction of HAART. Numbers strongly

Conclusions

Antiretroviral therapy restores the CD4+ T cell compartment and confers protection against opportunistic pathogens. Despite the controversies about which mechanisms are involved, many factors are certainly at work. Three mechanisms allow CD4+ T cell recovery: redistribution of memory CD4+ T cells from tissues, regeneration of naı̈ve T cells from the thymus and reduction of the inflammatory syndrome. Lack of restoration of a solid immunity against HIV itself is currently the major drawback of

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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