title: Molecular programming of endothelin-1 in HIV-infected brain: role of Tat in up-regulation of ET-1 and its inhibition by statins.
abstract: Human Immune Deficiency Virus-1 (HIV-1) infection can induce severe and debilitating neurological problems, including behavioral abnormalities, motor dysfunction, and dementia. HIV can persistently infect astrocytes, during which viral accessory proteins are produced that are unaffected by current antiretroviral therapy. The effect of these proteins on astrocyte function remains unknown. Astrocytes are the predominant cells within the brain; thus, disruption of astrocyte function could influence the neuropathogenesis of HIV infection. To explore further these effects, we constitutively expressed HIV-Tat protein in astrocytes. Since the nuclear presence of Tat protein leads to alteration of host gene expression, we further analyzed the effects of Tat on host gene transcripts. Endothelin-1 (ET-1) was a significantly elevated transcript as verified by reverse transcription-polymerase chain reaction (RT-PCR), and it was subsequently released extracellularly in Tat-expressing and HIV-infected astrocytes. ET-1 expression was also prominent in reactive astrocytes and neurons in brain tissues from basal ganglia and frontal lobes of HIV encephalitic patients. HIV-Tat regulated ET-1 at the transcriptional level through NF-kappaB (NF-kappaB)-responsive sites in the ET-1 promoter. Intriguingly, simvastatin (10 microM) down-regulated HIV-Tat-induced ET-1 and also inhibited activation of NF-kappaB in astrocytes. Our findings suggest that ET-1 may be critical in mediating the neuropathogenesis of HIV dementia and that statins may have therapeutic potential in these patients.
authors.affiliation: Department of Neurology, Richard Johnson Division of Neuro-Immunology and Neurological Infections, The Johns Hopkins University, 509 Pathology, 600 N. Wolfe St., Baltimore, MD 21287, USA. achauha1@jhmi.edu
authors.forename: Ashok
authors.initials: A
authors.lastname: Chauhan
authors.forename: Sven
authors.initials: S
authors.lastname: Hahn
authors.forename: Suzanne
authors.initials: S
authors.lastname: Gartner
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Pardo
authors.forename: Senthil Kumar
authors.initials: SK
authors.lastname: Netesan
authors.forename: Justin
authors.initials: J
authors.lastname: McArthur
authors.forename: Avindra
authors.initials: A
authors.lastname: Nath
mesh_terms: D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D018797:Cell Cycle Proteins / Q000378:metabolism* / Q000502:physiology; D019332:Endothelin-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000502:physiology; D015696:Gene Products, tat / Q000494:pharmacology*; D015658:HIV Infections / Q000378:metabolism*; D015497:HIV-1 / Q000737:chemistry; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D015850:Interleukin-6 / Q000494:pharmacology; D016209:Interleukin-8 / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D020648:Peptide Elongation Factor 1; D011401:Promoter Regions, Genetic / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation; D054322:tat Gene Products, Human Immunodeficiency Virus
chemical_list: D018797:Cell Cycle Proteins; C503234:EEF1A2 protein, human; D019332:Endothelin-1; D015696:Gene Products, tat; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; D020648:Peptide Elongation Factor 1; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D054322:tat Gene Products, Human Immunodeficiency Virus