Biochemical mechanisms of HIV induced T cell apoptosis

Selliah, Nithianandan; Finkel, Terri H.

doi:10.1038/sj.cdd.4400822

Cited by 75 publications

(58 citation statements)

References 137 publications

(54 reference statements)

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“…47 Analysis of T cells from patients infected with HIV, or of T cells infected in vitro with HIV, demonstrates a significant fraction of both infected and uninfected cells dying by apoptosis. 48 Between the many mechanisms that contribute to HIV-associated lymphocyte apoptosis, gp120/160 binding to the CD4 receptor is enclosed (reviewed in Roshal et al 6 ). On the basis of our previous report 43 in this study, we have explored the possibility that HIV-1-induced proneness to apoptotic mechanisms could be due to the gp120-mediated ezrin activation, and ezrin-to-CD95 association, in human resting T cells.…”

Section: Discussionmentioning

confidence: 99%

CD95/phosphorylated ezrin association underlies HIV-1 GP120/IL-2-induced susceptibility to CD95(APO-1/Fas)-mediated apoptosis of human resting CD4+T lymphocytes

et al. 2004

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CD95(APO-1/Fas)-mediated apoptosis of bystander uninfected T cells exerts a major role in the HIV-1-mediated CD4 þ T-cell depletion. HIV-1 gp120 has a key role in the induction of sensitivity of human lymphocytes to CD95-mediated apoptosis through its interaction with the CD4 receptor. Recently, we have shown the importance of CD95/ezrin/actin association in CD95-mediated apoptosis. In this study, we explored the hypothesis that the gp120-mediated CD4 engagement could be involved in the induction of susceptibility of primary human T lymphocytes to CD95-mediated apoptosis through ezrin phosphorylation and ezrin-to-CD95 association. Here, we show that gp120/IL-2 combined stimuli, as well as the direct CD4 triggering, on human primary CD4 þ T lymphocytes induced an early and stable ezrin activation through phosphorylation, consistent with the induction of ezrin/CD95 association and susceptibility to CD95-mediated apoptosis. Our results provide a new mechanism through which HIV-1-gp120 may predispose resting CD4 þ T cell to bystander CD95-mediated apoptosis and support the key role of ezrin/CD95 linkage in regulating susceptibility to CD95-mediated apoptosis.

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Section: Discussionmentioning

confidence: 99%

CD95/phosphorylated ezrin association underlies HIV-1 GP120/IL-2-induced susceptibility to CD95(APO-1/Fas)-mediated apoptosis of human resting CD4+T lymphocytes

et al. 2004

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“…NL4-3-induced Apoptosis Is ROS-dependent-ROS are known to induce multiple DNA lesions ranging from single base modifications to single strand DNA breaks and potentially lethal double strand DNA breaks (18,19). HIV-1-in- duced oxidative stress has been linked to apoptosis in macrophages and neurons (20,21).…”

Section: Resultsmentioning

confidence: 99%

Inhibition of p66ShcA Longevity Gene Rescues Podocytes from HIV-1-induced Oxidative Stress and Apoptosis

Husain

Meggs

Vashistha

et al. 2009

Journal of Biological Chemistry

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Glomerular visceral epithelial cells (podocytes) play a critical role in the pathogenesis of human immunodeficiency virus (HIV)-associated nephropathy.A key question concerns the mechanism(s) by which the HIV-1 genome alters the phenotype of the highly specialized, terminally differentiated podocytes. Here, using an in vitro system of conditionally immortalized differentiated human podocytes (CIDHPs), we document a pivotal role for the p66ShcA protein in HIV-1-induced reactive oxygen species generation and CIDHP apoptosis. CIDHP transfected with truncated HIV-1 construct (NL4-3) exhibit increased reactive oxygen species metabolism, DNA strand breaks, and a 5-fold increase in apoptosis, whereas the opposite was true for NL4-3/CIDHP co-transfected with mu-36p66ShcA (mu-36) dominant negative expression vector or isoform-specific p66-small interfering RNA. Phosphorylation at Ser-36 of the wild type p66ShcA protein, required for p66ShcA redox function and inhibition of the potent stress response regulator Foxo3a, was unchanged in mu-36/NL4-3/CIDHP but increased in NL4-3/CIDHP. Acute knockdown of Foxo3a by small interfering RNA induced a 50% increase in mu-36/NL4-3/CIDHP apoptosis, indicating that Foxo3a-dependent responses promote the survival phenotype in mu-36 cells. We conclude that inhibition of p66ShcA redox activity prevents generation of HIV-1 stress signals and activation of the CIDHP apoptosis program.Glomerular visceral epithelial cells or podocytes are highly specialized cells that play a pivotal role in the pathogenesis of focal segmental glomerular sclerosis (FSGS) and the collapsing variant of this entity, frequently encountered in HIVAN. The podocyte, strategically positioned along the glomerular basement membrane, is a critical component of the glomerular filtration barrier, functioning in tandem with its associated slit diaphragm to limit passage of albumin and plasma proteins to the urinary space (1, 2). Compelling evidence (3-7) supports a key role for HIV-1 gene products in the podocyte injury that leads to a breach in the integrity of the glomerular filtration barrier and the massive proteinuria that characterizes HIVAN. The absence of podocyte regeneration after cell injury or apoptosis is a major limitation to the development of innovative therapeutic strategies to arrest or prevent HIVAN and other glomerular diseases. Accordingly, interventions that increase the resistance of this terminally differentiated cell population to death signals offer a novel approach to preserve the integrity and permselectivity of the glomerular filtration barrier.Several lines of evidence support a dominant role for the p66ShcA protein in the intracellular pathways that convert oxidative stress to apoptosis (8, 9). The three overlapping Shc proteins, p66ShcA, p52ShcA, and p46ShcA, share a C-terminal Src homology 2 domain, central collagen homology region, and N-terminal phosphotyrosine binding domain. p46ShcA and p52ShcA are the product of alternative translation initiation sites within the same transcript, wherea...

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“…29,123 These proteins could potentially induce apoptosis of HIV-specific CD8 þ T cells either through a direct or an indirect mechanism. Physical interaction between HIV proteins and chemokine receptors expressed in CD8 þ T cells could be such a direct mechanism.…”

Section: Proapoptotic Activity Of Hiv Proteinsmentioning

confidence: 99%

“…A large body of studies has focused on the molecular mechanisms mediating apoptosis of infected as well as uninfected CD4 þ T cells revealing the importance of HIV-specific proteins in this process. 123,146 In the case of CD8 þ T cells, however, little information is available and one should be careful in extrapolating conclusions from studies concerning total CD8 þ T-cell apoptosis to the mechanisms that control HIVspecific CD8 þ T-cell apoptosis.…”

Section: Toward Understanding the Molecular Mechanism Of Hiv-specificmentioning

confidence: 99%

Apoptosis of HIV-specific CD8+ T cells: an HIV evasion strategy

2005

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Biochemical mechanisms of HIV induced T cell apoptosis

Cited by 75 publications

References 137 publications

CD95/phosphorylated ezrin association underlies HIV-1 GP120/IL-2-induced susceptibility to CD95(APO-1/Fas)-mediated apoptosis of human resting CD4+T lymphocytes

CD95/phosphorylated ezrin association underlies HIV-1 GP120/IL-2-induced susceptibility to CD95(APO-1/Fas)-mediated apoptosis of human resting CD4+T lymphocytes

Inhibition of p66ShcA Longevity Gene Rescues Podocytes from HIV-1-induced Oxidative Stress and Apoptosis

Apoptosis of HIV-specific CD8+ T cells: an HIV evasion strategy

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