Is HIV infection a TNF receptor signalling-driven disease?

doi:10.1016/j.it.2007.10.008

Trends in Immunology

Volume 29, Issue 2, February 2008, Pages 61-67

https://doi.org/10.1016/j.it.2007.10.008 Get rights and content

Recent studies indicate that TNF (tumor necrosis factor) receptor signalling is a key player in HIV infection. HIV proteins have been shown to target TNF receptor signalling, leading both to apoptosis of uninfected bystander T cells and to sustained viral replication in infected T cells and macrophages. This article proposes a model that highlights the role of HIV proteins in the modulation of TNF receptor signalling and could explain both immune suppression and the formation of viral reservoirs during HIV infection.

Introduction

The progressive depletion of both CD4⁺ and CD8⁺ T cells and the formation of viral reservoirs are two of the hallmarks of human immunodeficiency virus (HIV) infection [1]. Aside from a Th1-Th2 switch, AIDS pathogenesis could be explained by an immune dysregulation involving proinflammatory cytokines, especially tumor necrosis factor (TNF) α (TNF). TNF is secreted by activated macrophages and lymphocytes and induces diverse responses, including inflammation and apoptosis [2]. TNF binds to the cell transmembrane receptors TNFR1 and TNFR2, mainly to modulate immunity (Box 1). Microbial pathogens have evolved several mechanisms by which to modulate host responses mounted by TNF [3]. Even though two decades have now elapsed since the identification of HIV as the cause of acquired immunodeficiency syndrome (AIDS), knowledge about how HIV affects TNF receptor (TNFR) signalling is only now starting to emerge, and sometimes in contradictory ways. On the one hand, TNF is directly or indirectly involved in the modulation of T cell apoptosis via members of the TNFR superfamily, such as TNFR1, TNFR2, and Fas, whereas on the other hand, TNF stimulates HIV-1 replication in infected cells 4, 5, 6. In addition, HIV-1 proteins target the TNFR signalling pathway, modulating gene expression, especially HIV long terminal repeat (LTR) stimulation and T cell apoptosis, leading, in turn, both to immune suppression and to the formation of viral reservoirs in HIV infection. Therefore, targeting the TNFR signalling pathway might confer a crucial advantage to HIV via increased viral replication in the context of immune suppression.

Section snippets

In the early stages of infection, HIV proteins mimic TNFR signalling and favour sustained viral growth

In the early stages of HIV infection, and in the context of low levels of plasma TNF 5, 7, 8, virally encoded proteins, particularly Nef, Vpr, and Tat, mimic TNFR signalling, resulting in sustained viral growth within infected cells, especially macrophages (Figure 1).

Nef is a 27 kDa myristoylated protein that is expressed early during the virus life cycle and modulates several signalling pathways. The Nef protein mimics TNFR signalling, especially in monocytic cells and primary macrophages,

HIV proteins favour inhibition of T cell apoptosis through interference with TNFR signalling

HIV proteins favour persistence of the virus not only through activation of LTR activity, but also through inhibition of host cell apoptosis (Figure 1). In fact, the inhibition of apoptosis in HIV-1-infected T cells enhances virus production and facilitates persistent infection [22]. Both viral and cellular factors are involved in the controlled and sustained production of virions in infected CD4⁺ T lymphocytes in the vicinity of macrophages [23], and they could expand the viral reservoir and

HIV proteins favour immune suppression through the enhancement of TNFR signalling in the late stages of disease

In late stages of the disease, high levels of TNF are produced, resulting in dramatic TNF-mediated death of uninfected T cells and subsequent major immune suppression 5, 31. HIV proteins, such as gp120 and Vpu, might further participate in immune failure by enhancing the cytopathic effects mediated through TNFR signalling.

In vitro culture models demonstrate that uninfected CD4⁺ T cells undergo apoptosis upon contact with HIV-infected cells, such as mononuclear phagocytes. Macrophages play a

Model of HIV pathogenesis based on modulation of TNFR signalling by HIV proteins: from TNF mimicry to enhancement of TNF activity

Because of the various effects of HIV proteins on TNF signalling and apoptosis (Table 1), we would like to present a new, to our knowledge, model that highlights the role of TNFR signalling in the modulation of both T cell apoptosis and viral persistence and could thereby further enhance our understanding of the pathogenesis of HIV-mediated disease (Figure 2).

Early in the disease, when the levels of proinflammatory proteins and C-C chemokines are low and chronic immune activation is not yet

Conclusion

The formation of viral reservoirs and the loss of T lymphocytes are central factors in the progression of HIV. TNF favours HIV replication and can induce apoptosis, and, interestingly, several HIV-1 proteins share similar functions. HIV-1 proteins mimic, interfere with, or enhance TNFR signalling at different stages of the disease and therefore represent potential targets that could ultimately lead to new treatments controlling both viral replication and immune activation in HIV-infected

Acknowledgements

We thank Aurelie Vacheret for secretarial assistance. Support was provided by grants from Franche-Comté University (to G.H.), from Societe Francaise D’Exportation des Ressources Educatives, and from the Higher Education Commission, Pakistan (to K.A.K.).

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Trends in Immunology

OpinionIs HIV infection a TNF receptor signalling-driven disease?

Introduction

Section snippets

In the early stages of infection, HIV proteins mimic TNFR signalling and favour sustained viral growth

HIV proteins favour inhibition of T cell apoptosis through interference with TNFR signalling

HIV proteins favour immune suppression through the enhancement of TNFR signalling in the late stages of disease

Model of HIV pathogenesis based on modulation of TNFR signalling by HIV proteins: from TNF mimicry to enhancement of TNF activity

Conclusion

Acknowledgements

Immunity

Blood

Clin. Microbiol. Infect.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Trends Immunol.

Cell

Virology

Blood

J. Biol. Chem.

J. Biol. Chem.

Trends Immunol.

Blood

Exp. Cell Res.

Blood

J. Biol. Chem.

Host factors and the pathogenesis of HIV-induced disease

Nature

Modulation of tumor necrosis factor by microbial pathogens

PLoS Pathog.

Macrophage-dependent apoptosis of CD4+ T lymphocytes from HIV-infected individuals is mediated by FasL and tumor necrosis factor

J. Exp. Med.

Signalling pathways of the TNF superfamily: a double-edged sword

Nat. Rev. Immunol.

Serum levels of tumor necrosis factor-α (TNF α) and soluble TNF receptors in human immunodeficiency virus type 1 infection–correlations to clinical, immunologic, and virologic parameters

J. Infect. Dis.

HIV-1 Nef induces the release of inflammatory factors from human monocyte/macrophages: involvement of Nef endocytotic signals and NF-κB activation

J. Immunol.

In vitro treatment of human monocytes/macrophages with myristoylated recombinant Nef of human immunodeficiency virus type 1 leads to the activation of mitogen-activated protein kinases, IκB kinases, and interferon regulatory factor 3 and to the release of β interferon

J. Virol.

The role of Vpr in HIV-1 pathogenesis

Curr. HIV Res.

Human immunodeficiency virus type 1 (HIV-1) accessory protein Vpr induces transcription of the HIV-1 and glucocorticoid-responsive promoters by binding directly to p300/CBP coactivators

J. Virol.

HIV-Tat protein activates c-Jun N-terminal kinase and activator protein-1

J. Immunol.

Tat gets the ‘green’ light on transcription initiation

Retrovirology

HIV-1 Vpr and anti-inflammatory activity

DNA Cell Biol.

HIV-1 Vpr regulates expression of β chemokines in human primary lymphocytes and macrophages

J. Leukoc. Biol.

Opinion
Is HIV infection a TNF receptor signalling-driven disease?

Macrophage-dependent apoptosis of CD4⁺ T lymphocytes from HIV-infected individuals is mediated by FasL and tumor necrosis factor