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Curcio, Marli F. ^[1] ; Batista, Wagner L. ^{[2, 3]} ; Castro, Eloisa D. ^[4] ; Strumillo, Scheilla T. ^[4] ; Ogata, Fernando T. ^[5] ; Alkmim, Wagner ^[2] ; Brunialti, Milena K. C. ^[1] ; Salomao, Reinaldo ^[1] ; Turcato, Gilberto ^[1] ; Diaz, Ricardo S. ^[1] ; Monteiro, Hugo P. ^[4] ; Janini, Luiz Mario R. ^{[2, 1]}

Afiliação do(s) autor(es)

^[1] Univ Fed Sao Paulo, Dept Med Infect Dis, Rua Pedro de Toledo 781, BR-04039032 Sao Paulo, SP - Brazil

^[2] Univ Fed Sao Paulo, Dept Microbiol Immunol & Parasitol, Sao Paulo, SP - Brazil

^[3] Univ Fed Sao Paulo, Dept Pharmaceut Sci, Diadema - Brazil

^[4] Univ Fed Sao Paulo, Dept Biochem Mol Biol, CTCMol, Sao Paulo, SP - Brazil

^[5] Univ Paulista, Struct & Funct Ecol Ecosyst, Sorocaba - Brazil

• Tipo de documento: Artigo Científico
• Fonte: NITRIC OXIDE-BIOLOGY AND CHEMISTRY; v. 93, p. 78-89, DEC 1 2019.
• Citações Web of Science: 0

Resumo

Human immunodeficiency virus (HIV) infections are typically accompanied by high levels of secreted inflammatory cytokines and generation of high levels of reactive oxygen species (ROS). To elucidate how HIV-1 alters the cellular redox environment during viral replication, we used human HIV-1 infected CD4(+)T lymphocytes and uninfected cells as controls. ROS and nitric oxide (NO) generation, antioxidant enzyme activity, protein phosphorylation, and viral and proviral loads were measured at different times (2-36 h post-infection) in the presence and absence of the NO donor S-nitroso-N-acetylpenicillamine (SNAP). HIV-1 infection increased ROS generation and decreased intracellular NO content. Upon infection, we observed increases in copper/zinc superoxide dismutase (SOD1) and glutathione peroxidase (GPx) activities, and a marked decrease in glutathione (GSH) concentration. Exposure of HIV-1 infected CD4(+)T lymphocytes to SNAP resulted in an increasingly oxidizing intracellular environment, associated with tyrosine nitration and SOD1 inhibition. In addition, SNAP treatment promoted phosphorylation and activation of the host's signaling proteins, PKC, Src kinase and Akt. Inhibition of PKC leads to inhibition of Src kinase strongly suggesting that PKC is the upstream element in this signaling cascade. Changes in the intracellular redox environment after SNAP treatment had an effect on HIV-1 replication as reflected by increases in proviral and viral loads. In the absence or presence of SNAP, we observed a decrease in viral load in infected CD4(+)T lymphocytes pre-incubated with the PKC inhibitor GF109203X. In conclusion, oxidative/nitrosative stress conditions derived from exposure of HIV-1-infected CD4(+)T lymphocytes to an exogenous NO source trigger a signaling cascade involving PKC, Src kinase and Akt. Activation of this signaling cascade appears to be critical to the establishment of HIV-1 infection. (AU)

• Processo FAPESP: 10/09366-0 - Alterações do Ambiente Redox Intracelular durante a Infecção pelo Vírus da Imunodeficiência Humana tipo I (HIV-1) Associadas à Ativação de Src Quinases
• Beneficiário: Marli Ferreira Curcio
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 10/07236-1 - Vírus como agentes modificadores do ambiente celular.
• Beneficiário: Luiz Mário Ramos Janini
• Modalidade de apoio: Auxílio à Pesquisa - Regular