Apoptosis induced by HIV‐gp120 in a Th1 clone involves the generation of reactive oxygen intermediates downstream CD95 triggering

Radrizzani, Marina; Accornero, Paola; Delia, Domenico; Kurrle, R.; Colombo, Mario P.

doi:10.1016/s0014-5793(97)00672-8

Cited by 12 publications

(8 citation statements)

References 43 publications

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“…Infected individuals also express elevated serum levels of the lipid peroxidation products malondialdehyde and hydroperoxide [14-16]. HIV infected cells demonstrate reduced levels of thioredoxin (a thiol antioxidant) [17], and the HIV proteins gp120 [8, 18-22], Vpr [10, 23], and Tat [9, 18] can directly induce cellular oxidative stress. Oxidative stress within infected cells can promote HIV replication through nuclear factor-kappa B (NF-κB)-driven transcriptional regulation [24-26] and inflammatory cytokine release [24, 27-31], thereby perpetuating systemic immune activation and disease progression.…”

Section: Oxidative Stress In Hiv Infectionmentioning

confidence: 99%

Heme Oxygenase-1 Dysregulation in the Brain: Implications for HIVAssociated Neurocognitive Disorders

Ambegaokar¹,

Kolson

2014

CHR

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Heme oxygenase-1 (HO-1) is a highly inducible and ubiquitous cellular enzyme that subserves cytoprotective responses to toxic insults, including inflammation and oxidative stress. In neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease and multiple sclerosis, HO-1 expression is increased, presumably reflecting an endogenous neuroprotective response against ongoing cellular injury. In contrast, we have found that in human immunodeficiency virus (HIV) infection of the brain, which is also associated with inflammation, oxidative stress and neurodegeneration, HO-1 expression is decreased, likely reflecting a unique role for HO-1 deficiency in neurodegeneration pathways activated by HIV infection. We have also shown that HO-1 expression is significantly suppressed by HIV replication in cultured macrophages which represent the primary cellular reservoir for HIV in the brain. HO-1 deficiency is associated with release of neurotoxic levels of glutamate from both HIV-infected and immune-activated macrophages; this glutamate-mediated neurotoxicity is suppressed by pharmacological induction of HO-1 expression in the macrophages. Thus, HO-1 induction could be a therapeutic strategy for neuroprotection against HIV infection and other neuroinflammatory brain diseases. Here, we review various stimuli and signaling pathways regulating HO-1 expression in macrophages, which could promote neuronal survival through HO-1-modulation of endogenous antioxidant and immune modulatory pathways, thus limiting the oxidative stress that can promote HIV disease progression in the CNS. The use of pharmacological inducers of endogenous HO-1 expression as potential adjunctive neuroprotective therapeutics in HIV infection is also discussed.

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Section: Oxidative Stress In Hiv Infectionmentioning

confidence: 99%

Heme Oxygenase-1 Dysregulation in the Brain: Implications for HIVAssociated Neurocognitive Disorders

Ambegaokar¹,

Kolson

2014

CHR

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“…However, ligation with CD4 is not required, and of the coreceptors, gp120 signaling through CXCR4 is a more potent apoptotic stimulus than CCR5. Several mechanisms have been proposed for gp120's proapoptotic effect, including through upregulation of Fas, FasL, and TNF α expression; 40 molecular mimicry with Fas; 41 upregulation of TRAIL receptors DR4 and DR5; 42 induction of cell cycle arrest at the G2 phase; 43 generation of reactive oxygen intermediates; 44 reduced expression of Bcl-2; 45 phosphorylation of mTOR and p53; 46 increased expression of the proapoptotic protein PUMA; 47 and activation of p38. 48 Membrane-bound Gp120 may also induce apoptosis through syncytia formation, although the role of syncytia formation in in vivo infection is controversial.…”

Section: Mediators Of Apoptosis In Hiv Diseasementioning

confidence: 99%

Mechanisms of HIV-associated lymphocyte apoptosis: 2010

2010

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The inevitable decline of CD4T cells in untreated infection with the Human immunodeficiency virus (HIV) is due in large part to apoptosis, one type of programmed cell death. There is accumulating evidence that the accelerated apoptosis of CD4T cells in HIV infection is multifactorial, with direct viral cytotoxicity, signaling events triggered by viral proteins and aberrant immune activation adding to normal immune defense mechanisms to contribute to this phenomenon. Current antiviral treatment strategies generally lead to reduced apoptosis, but this approach may come at the cost of preserving latent viral reservoirs. It is the purpose of this review to provide an update on the current understanding of the role and mechanisms of accelerated apoptosis of T cells in the immunopathogenesis of HIV infection, and to highlight potential ways in which this seemingly deleterious process could be harnessed to not just control, but treat HIV infection.

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“…220–222 These early findings were supported by later studies demonstrating reduced levels of thioredoxin (a thiol antioxidant) in HIV-infected cells 223 and elevated serum levels of the lipid peroxidation products malondialdehyde 224, 225 and lipid hydroperoxides 226 in HIV-infected individuals. Moreover, the HIV proteins gp120, 216, 219, 227–230 Vpr, 218, 231 and Tat 217, 219 have been directly implicated in the induction of cellular oxidative stress. Oxidative stress in turn can drive NF-κB-driven HIV replication 232–234 and inflammatory cytokine release, 232, 235–239 thus perpetuating chronic systemic immune activation and disease progression in HIV-infected individuals.…”

Section: Faes As Adjunctive Therapy For Hiv Infectionmentioning

confidence: 99%

Dimethyl Fumarate Modulation of Immune and Antioxidant Responses: Application to HIV Therapy

Gill

Kolson

2013

Crit Rev Immunol

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The persistence of chronic immune activation and oxidative stress in human immunodeficiency virus (HIV)-infected, antiretroviral drug-treated individuals are major obstacles to fully preventing HIV disease progression. The immune modulator and antioxidant dimethyl fumarate (DMF) is effective in treating immune-mediated diseases and it also has potential applications to limiting HIV disease progression. Among the relevant effects of DMF and its active metabolite monomethyl fumarate (MMF) are induction of a Th1 → Th2 lymphocyte shift, inhibition of pro-inflammatory cytokine signaling, inhibition of NF-κB nuclear translocation, inhibition of dendritic cell maturation, suppression of lymphocyte and endothelial cell adhesion molecule expression, and induction of the Nrf2-dependent antioxidant response element (ARE) and effector genes. Associated with these effects are reduced lymphocyte and monocyte infiltration into psoriatic skin lesions in humans and immune-mediated demyelinating brain lesions in rodents, which confirms potent systemic and central nervous system (CNS) effects. In addition, DMF and MMF limit HIV infection in macrophages in vitro, albeit by unknown mechanisms. Finally, DMF and MMF also suppress neurotoxin production from HIV-infected macrophages, which drives CNS neurodegeneration. Thus, DMF might protect against systemic and CNS complications in HIV infection through its effective suppression of immune activation, oxidative stress, HIV replication, and macrophage-associated neuronal injury.

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Apoptosis induced by HIV‐gp120 in a Th1 clone involves the generation of reactive oxygen intermediates downstream CD95 triggering

Cited by 12 publications

References 43 publications

Heme Oxygenase-1 Dysregulation in the Brain: Implications for HIVAssociated Neurocognitive Disorders

Heme Oxygenase-1 Dysregulation in the Brain: Implications for HIVAssociated Neurocognitive Disorders

Mechanisms of HIV-associated lymphocyte apoptosis: 2010

Dimethyl Fumarate Modulation of Immune and Antioxidant Responses: Application to HIV Therapy

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