RESUMO
AIMS: Human immunodeficiency virus (HIV) infection induces oxidative stress and alcohol use accelerates disease progression, subsequently causing immune dysfunction. However, HIV and alcohol impact on lipid rafts-mediated immune dysfunction remains unknown. In this study, we investigate the modulation by which oxidative stress induces reactive oxygen species (ROS) affecting redox expression, lipid rafts caveiloin-1, ATP-binding cassette (ABC) transporters, and transcriptional sterol regulatory element-binding protein (SREBP) gene and protein modification and how these mechanisms are associated with arachidonic acid (AA) metabolites in HIV positive alcohol users, and how they escalate immune dysfunction. RESULTS: In both alcohol using HIV-positive human subjects and in vitro studies of alcohol with HIV-1 gp120 protein in peripheral blood mononuclear cells, increased ROS production significantly affected redox expression in glutathione synthetase (GSS), super oxide dismutase (SOD), and glutathione peroxidase (GPx), and subsequently impacted lipid rafts Cav-1, ABC transporters ABCA1, ABCG1, ABCB1, and ABCG4, and SREBP transcription. The increased level of rate-limiting enzyme 3-hydroxy-3-methylglutaryl HMG-CoA reductase (HMGCR), subsequently, inhibited 7-dehydrocholesterol reductase (DHCR-7). Moreover, the expression of cyclooxygenase-2 (COX-2) and lipoxygenase-5 (5-LOX) mRNA and protein modification tentatively increased the levels of prostaglandin E2 synthases (PGE2) in plasma when compared with either HIV or alcohol alone. INNOVATION: This article suggests for the first time that the redox inhibition affects lipid rafts, ABC-transporter, and SREBP transcription and modulates AA metabolites, serving as an important intermediate signaling network during immune cell dysfunction in HIV-positive alcohol users. CONCLUSION: These findings indicate that HIV infection induces oxidative stress and redox inhibition, affecting lipid rafts and ABC transports, subsequently upregulating AA metabolites and leading to immune toxicity, and further exacerbation with alcohol use. Antioxid. Redox Signal. 28, 324-337.
Assuntos
Álcoois/toxicidade , Araquidonato 5-Lipoxigenase/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Infecções por HIV/metabolismo , Adulto , Álcoois/imunologia , Álcoois/metabolismo , Araquidonato 5-Lipoxigenase/genética , Ácido Araquidônico/genética , Ácido Araquidônico/metabolismo , Doadores de Sangue , Ciclo-Oxigenase 2/genética , Progressão da Doença , Feminino , Regulação da Expressão Gênica/imunologia , Glutationa Peroxidase/genética , Glutationa Sintase/genética , HIV/efeitos dos fármacos , HIV/imunologia , HIV/patogenicidade , Infecções por HIV/imunologia , Infecções por HIV/patologia , Infecções por HIV/virologia , Humanos , Masculino , Microdomínios da Membrana/efeitos dos fármacos , Microdomínios da Membrana/imunologia , Microdomínios da Membrana/virologia , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/imunologia , Espécies Reativas de Oxigênio/metabolismo , Proteínas de Ligação a Elemento Regulador de Esterol/genética , Superóxido Dismutase/genéticaRESUMO
Earlier studies have established that infection with HIV-1 subtypes (clades) might differentially influence the neuropathogenesis of HIV-1-associated neurocognitive dysfunction (HAND). HIV-1 Trans activator of transcription protein (Tat) is of considerable significance and plays a major role in the central nervous system (CNS) dysfunction. However, these HIV-1 clades exert diverse cellular effects that leads to neuropathogenic dysfunction has not been well established. We hypothesized that the HIV-1 clade B and clade C Tat proteins effect synaptic plasticity expression in neuroblastoma cells (SK-N-MC) by diverse methods, and accordingly modulates the development of HAND. In the present study, we have analyzed important and highly expressed 84 key human synaptic plasticity genes expression which differentially impact in clade B and clade C Tat treated SK-N-MC cells using RT(2) Profile PCR Array human Synaptic Plasticity kit. Observed results demonstrate that out of 84 key synaptic plasticity genes, 36 and 25 synaptic genes were substantially (≥3 fold) up-regulated and 5 and 5 genes considerably (≥3 fold) down-regulated in clade B and clade C Tat treated cells, respectively, compared to the control SK-N-MC. We have also estimated the levels of glutamine and glutamate in HIV-1 clade B and C Tat exposed SK-N-MC cells compared to untreated cells. Our results indicate that levels of glutamate, glutamine and expression of synaptic plasticity genes were highly dysregulated by HIV-1 clade B Tat compared to clade C Tat in SK-N-MC cells. In summary, this study suggests that clade B Tat substantially potentiates neuronal toxicity and further dysregulated synaptic plasticity genes in SK-N-MC may contribute to the severe neuropathogenesis linked with HAND.