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  • Review Article
  • Published:

Cell death and immunity

Apoptosis as an HIV strategy to escape immune attack

Nature Reviews Immunology volume 3, pages 392–404 (2003)Cite this article

Key Points

  • Mechanisms that contribute to CD4+ T-cell lymphopaenia during the chronic phase of HIV-infection are complex. They include increased T-cell turnover and accelerated HIV-driven destruction of infected and bystander uninfected cells, and inappropriate T-cell renewal as a result of HIV interference with thymic differentiation and homeostatic proliferation.

  • HIV-infection activates the two main pathways of cell death in lymphocytes: activation-induced cell death (AICD) through the tumour-necrosis factor (TNF) family of death receptors and activated T-cell autonomous death (ACAD) through BCL-2-related proteins and mitochondrion.

  • The intensity of cell death is correlated with the pathogenicity of the infection and with disease progression and it is closely linked to HIV-driven generalized immune activation.

  • HIV-encoded products (gp120, Nef, Tat, Vpu, Vpr and protease) are involved in the control of cell death in the host, either by triggering the death receptor pathways — upregulation of Fas (CD95)–FasL (CD95L) and TNFR–TNF/TRAIL pathways — or by acting through the mitochondrial pathway — phosphorylation of p53, upregulation of expression of BAX (BCL-2-associated X protein), dissipation of mitochondrial transmembrane potential and cytochrome c release, and activation of caspases.

  • The functional consequence of HIV-driven apoptosis is the impairment of HIV-specific immunity, which results from the apoptosis of virus-specific CD4+ T helper cells, subsequent decreased synthesis of type-1 cytokines and altered differentiation and activity of HIV-specific CD8+ cytotoxic T lymphocytes.

  • Suppression of virus replication by potent anti-retroviral therapy can partly restore CD4+ T-cell numbers and functions. Quantitative restoration involves several phases, including decreased HIV-driven lymphocyte apoptosis, homeostatic proliferation and reconstitution of the naive T-cell pool by increased thymic output. Qualitative restoration is incomplete and new strategies, such as immune-based therapy, are presently under investigation to boost HIV-specific immunity.

Abstract

Viruses have evolved numerous mechanisms to evade the host immune system and one of the strategies developed by HIV is to activate apoptotic programmes that destroy immune effectors. Not only does the HIV genome encode pro-apoptotic proteins, which kill both infected and uninfected lymphocytes through either members of the tumour-necrosis factor family or the mitochondrial pathway, but it also creates a state of chronic immune activation that is responsible for the exacerbation of physiological mechanisms of clonal deletion. This review discusses the molecular mechanisms by which HIV manipulates the apoptotic machinery to its advantage, assesses the functional consequences of this process and evaluates how new therapeutics might counteract this strategy.

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Figure 1: T-cell homeostasis in HIV infection.
Figure 2: Apoptotic pathways triggered by HIV in infected cells.
Figure 3: Relationship between virus-mediated immune activation, T-cell apoptosis and disease progression before and after anti-retroviral therapy.
Figure 4: Functional consequences of inappropriate T-cell apoptosis.

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Acknowledgements

I would like to thank my past and present colleagues for their contribution to this work and apologize to all colleagues whose work has not been cited in this review due to space restrictions. This work was supported by grants from the Agence Nationale de Recherche sur le SIDA (ANRS), Ensemble contre le SIDA (Sidaction), the CNRS, Centre National de la Recherche Scientifique, Pasteur Institute and the European Union.

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  1. Department of Molecular Medicine, Antiviral Immunity, Biotherapy and Vaccine Unit, Pasteur Institute, 28 Rue du Dr Roux, Paris, 75724 Cedex 15, France

    Marie-Lise Gougeon

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DATABASES

LocusLink

BAX

BCL-2

caspase-8

CD34

CD70

CD95

CD95L

CDK1

FLIP

CXCR4

cyclin B

Env

ICE

IFN-γ

IL-2

IL-4

IL-7

IL-10

IL-12

IL-15

MIP1β

Nef

p53

MTOR

RIP

SDF1

Tat

TGF-β

TNF

TNFR1

TNFR2

TRADD

TRAF2

TRAIL/APO2L

Vpr

Vpu

Glossary

BROMODEOXYURIDINE

(BrdU). A thymidine analogue that is incorporated into DNA during DNA replication. Cells that have incorporated BrdU, and presumably have divided, can be visualized by flow cytometry using antibodies specific for BrdU.

DEUTERATED GLUCOSE

Newly synthesized nucleotide that is generated from deuterium (2H)-labelled glucose can be used to label DNA that is synthesized during the administration period of the labelling molecule. Cells of interest can be purified by fluorescence-activated cell sorting, and the isotopic enrichment of cellular DNA content is assessed by gas chromatography and mass spectrometry. Using a mathematical model to analyse the data, the proliferation rate and half-life of cell populations can be calculated.

SYNCYTIA

Multinucleated giant cells that are formed following the fusion of infected cells expressing HIV-encoded envelope glycoproteins and uninfected cells expressing the CD4 co-receptor. The resulting syncytia subsequently undergo apoptosis.

HU-PBL-NOD-SCID MICE

A humanized mouse model in which human peripheral-blood lymphocytes (PBLs) are transplanted into non-obese diabetic (NOD)-severe combined immunodeficient (SCID) mice. This model can be used to examine in vivo apoptosis after HIV-1 infection.

FRATRICIDE

A form of cell killing in which one of a group of similar cells kills another member or members of the group.

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Gougeon, ML. Apoptosis as an HIV strategy to escape immune attack. Nat Rev Immunol 3, 392–404 (2003). https://doi.org/10.1038/nri1087

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