RESUMO
Human immunodeficiency virus (HIV-1) utilizes the NF-kappaB/Rel proteins to regulate transcription through NF-kappaB binding sites in the HIV-1 long terminal repeat (LTR). Normally, NF-kappaB is retained in the cytoplasm by inhibitory IkappaB proteins; after stimulation by multiple activators including viruses, IkappaBalpha is phosphorylated and degraded, resulting in NF-kappaB release. In the present study, we examined the effect of tetracycline-inducible expression of transdominant repressors of IkappaBalpha (TD-IkappaBalpha) on HIV-1 multiplication using stably selected Jurkat T cells. TD-IkappaBalpha was inducibly expressed as early as 3 h after doxycycline addition and dramatically reduced both NF-kappaB DNA binding activity and LTR-directed gene activity. Interestingly, induced TD-IkappaBalpha expression also decreased endogenous IkappaBalpha expression to undetectable levels by 24 h after induction, demonstrating that TD-IkappaBalpha repressed endogenous NF-kappaB-dependent gene transcription. TD-IkappaBalpha expression also sensitized Jurkat cells to tumor necrosis factor-induced apoptosis. De novo HIV-1 infection of Jurkat cells was dramatically altered by TD-IkappaBalpha induction, resulting in inhibition of HIV-1 multiplication, as measured by p24 antigen, reverse transcriptase, and viral RNA. Given the multiple functions of the NF-kappaB/IkappaB pathway, TD-IkappaBalpha expression may interfere with HIV-1 multiplication at several levels: LTR-mediated transcription, Rev-mediated export of viral RNA, inhibition of HIV-1-induced pro-inflammatory cytokines, and increased sensitivity of HIV-1-infected cells to apoptosis.
Assuntos
Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Ligação a DNA/genética , HIV-1/fisiologia , Proteínas I-kappa B , NF-kappa B/antagonistas & inibidores , Proteínas Repressoras/farmacologia , Replicação Viral/efeitos dos fármacos , Sequência de Aminoácidos , Antibacterianos/farmacologia , Apoptose , DNA Viral/efeitos dos fármacos , DNA Viral/metabolismo , Proteínas de Ligação a DNA/biossíntese , Regulação para Baixo/efeitos dos fármacos , Doxiciclina/farmacologia , Regulação Viral da Expressão Gênica/efeitos dos fármacos , Proteína do Núcleo p24 do HIV/metabolismo , Transcriptase Reversa do HIV/metabolismo , HIV-1/genética , Humanos , Células Jurkat , Dados de Sequência Molecular , Inibidor de NF-kappaB alfa , RNA Viral/efeitos dos fármacos , RNA Viral/metabolismo , Linfócitos T/virologiaRESUMO
Background: Intrauterine growth retardation, associated to hypertensive disease of pregnancy, is responsible for a higher perinatal mortality and morbidity. Aim: To assess obstetrical, perinatal and neonatal features of intrauterine growth retardation associated to hypertensive disease of pregnancy. Patients and methods: One hundred thirty seven newborns with intrauterine growth retardation, whose mothers had hypertensive disease of pregnancy, were compared to 165 similar newborns but whose mothers did not have the disease. Results: The incidence of intrauterine growth retardation associated to hypertensive disease of pregnancy was 45.4 percent. Maternal obesity at the start and end of pregnancy, a pregestational weight over 65 kg and a weight increment of more than 20 kg during pregnancy were risk factors for hypertensive disease of pregnancy with relative risks of 1.76, 1.62, 1.62 and 2.09 respectively. Relative risks for cesarean section and prematurity were also higher among women with hypertensive disease of pregnancy. Intrauterine growth retardation associated to maternal hypertension was symmetrical and severe in 37.9 percent of newborns. All seven neonatal deaths occurred in newborns with severe retardation. Conclusions: Neonatal and perinatal morbidity and mortality are higher in newborns with intrauterine growth retardation. Hypertensive disease of pregnancy was associated with a twice higher incidence of asymmetrical intrauterine growth retardation
