HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: fj.06-7054comv1 21/3/777    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chauhan, A. Articles by Nath, A. Search for Related Content PubMed PubMed Citation Articles by Chauhan, A. Articles by Nath, A.

Molecular programming of endothelin-1 in HIV-infected brain: role of Tat in up-regulation of ET-1 and its inhibition by statins

Ashok Chauhan^*,1, Sven Hahn^*, Suzanne Gartner^*, Carlos A. Pardo^*, Senthil Kumar Netesan^*, Justin McArthur^* and Avindra Nath^*,

Departments of
^* Neurology and

Neuroscience, The Johns Hopkins University, Baltimore, Maryland, USA

¹Correspondence: 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. E-mail: achauha1{at}jhmi.edu

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-B (NF-B)-responsive sites in the ET-1 promoter. Intriguingly, simvastatin (10 µM) down-regulated HIV-Tat-induced ET-1 and also inhibited activation of NF-B 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.—Chauhan, A., Hahn, S., Gartner, S., Pardo, C. A., Netesan, S. K., McArthur, J., Nath, A. Molecular programming of endothelin-1 in HIV-infected brain: role of Tat in up-regulation of ET-1 and its inhibition by statins.

Key Words: HIV-neuropathogenesis • nuclear Tat • ET-1 transcriptional regulation • NF-B • simvastatin

This article has been cited by other articles:

				I. E. Andras, G. Rha, W. Huang, S. Eum, P.-O. Couraud, I. A. Romero, B. Hennig, and M. Toborek Simvastatin Protects against Amyloid {beta} and HIV-1 Tat-Induced Promoter Activities of Inflammatory Genes in Brain Endothelial Cells Mol. Pharmacol., May 1, 2008; 73(5): 1424 - 1433. [Abstract] [Full Text] [PDF]