Interferon-α Regulates Glutaminase 1 Promoter through STAT1 Phosphorylation: Relevance to HIV-1 Associated Neurocognitive Disorders

HIV-1 associated neurocognitive disorders (HAND) develop during progressive HIV-1 infection and affect up to 50% of infected individuals. Activated microglia and macrophages are critical cell populations that are involved in the pathogenesis of HAND, which is specifically related to the production and release of various soluble neurotoxic factors including glutamate. In the central nervous system (CNS), glutamate is typically derived from glutamine by mitochondrial enzyme glutaminase. Our previous study has shown that glutaminase is upregulated in HIV-1 infected monocyte-derived-macrophages (MDM) and microglia. However, how HIV-1 leads to glutaminase upregulation, or how glutaminase expression is regulated in general, remains unclear. In this study, using a dual-luciferase reporter assay system, we demonstrated that interferon (IFN) α specifically activated the glutaminase 1 (GLS1) promoter. Furthermore, IFN-α treatment increased signal transducer and activator of transcription 1 (STAT1) phosphorylation and glutaminase mRNA and protein levels. IFN-α stimulation of GLS1 promoter activity correlated to STAT1 phosphorylation and was reduced by fludarabine, a chemical that inhibits STAT1 phosphorylation. Interestingly, STAT1 was found to directly bind to the GLS1 promoter in MDM, an effect that was dependent on STAT1 phosphorylation and significantly enhanced by IFN-α treatment. More importantly, HIV-1 infection increased STAT1 phosphorylation and STAT1 binding to the GLS1 promoter, which was associated with increased glutamate levels. The clinical relevance of these findings was further corroborated with investigation of post-mortem brain tissues. The glutaminase C (GAC, one isoform of GLS1) mRNA levels in HIV associated-dementia (HAD) individuals correlate with STAT1 (p<0.01), IFN-α (p<0.05) and IFN-β (p<0.01). Together, these data indicate that both HIV-1 infection and IFN-α treatment increase glutaminase expression through STAT1 phosphorylation and by binding to the GLS1 promoter. Since glutaminase is a potential component of elevated glutamate production during the pathogenesis of HAND, our data will help to identify additional therapeutic targets for the treatment of HAND

Experimental rotavirus diarrhoea in colostrum-deprived newborn calves: assay of treatment by administration of bacterially produced human interferon (Hu-IFN alpha 2).

Seven colostrum-deprived newborn calves were orally inoculated within 24 hours after birth with bovine rotavirus. Three of them were intramuscularly injected with bacterially produced human interferon (Hu-IFN alpha 2). The four control animals presented a severe diarrhoea for at least 48 hours, while only one of the treated calves suffered from a transient diarrhoea for a few hours. Hu-IFN alpha 2 seems therefore able to control rotavirus diarrhoea in newborn calves, although it did not inhibit virus excretion and seroconversion in the treated animals. Moreover, the administration of endogenous interferon appeared to be well tolerated by newborn calves. The efficacy of human alpha 2 interferon for the treatment of this important virus infection of cattle seems thus well established

Induction d'interféron au cours de l'infection du veau nouveau-né par le rotavirus : rôle possible dans le contrôle de la pathogénécité

Colostrum-deprived newborn calves were experimentally infected with cell-culture rotavirus. A similar process of infection was observed when the animals were inoculated immediately after birth or at the age of three days, with a corresponding delay in the onset of virus excretion and interferon production in the later case. With high doses of virus, interferon was produced very early and no symptoms were observed. With lower doses of virus, interferon production was delayed and preceded by a severe but transient diarrhoea. In all cases, several waves of interferon production were observed. Our data indicate that interferon plays an important role in the control of viral diseases in calves and in their natural recovery