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Journal of Virology, November 1998, p. 8797-8805, Vol. 72, No. 11
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

CD4 Promoter Transactivation by Human Herpesvirus 6

Louis Flamand,1,* Fabio Romerio,2 Marvin S. Reitz,2 and Robert C. Gallo2

Laboratory of Virology, Rheumatology and Immunology Research Center, Centre de Recherche du CHUL and Laval University, Sainte-Foy, Quebec, Canada,1 and Institute of Human Virology, University of Maryland, Baltimore, Maryland 212012

Received 26 February 1998/Accepted 4 August 1998

The observation that human herpesvirus 6 (HHV-6) can induce CD4 gene transcription and expression in CD4- cells was reported several years ago (P. Lusso, A. De Maria, M. Malnati, F. Lori, S. E. DeRocco, M. Baseler, and R. C. Gallo, Nature 349:533-535, 1991) and subsequently confirmed (P. Lusso, M. S. Malnati, A. Garzino-Demo, R. W. Crowley, E. O. Long, and R. C. Gallo, Nature 362:458-462, 1993; G. Furlini, M. Vignoli, E. Ramazzotti, M. C. Re, G. Visani, and M. LaPlaca, Blood 87:4737-4745, 1996). Our objective was to identify the mechanisms underlying such phenomena. Using reporter gene constructs driven by the CD4 promoter, we report that HHV-6 can efficiently transactivate such genetic elements. Activation of the CD4 promoter occurs in the presence of the viral DNA polymerase inhibitor phosphonoformic acid, which limits expression to the immediate-early and early classes of viral genes. Using deletion mutants and specific CD4 promoter mutants, we identified an ATF/CRE binding site located at nucleotides -67 to -60 upstream of the CD4 gene transcription start site that is important for HHV-6 transactivation. The ATF/CRE site is also essential for CD4 promoter activation by forskolin, an activator of adenylate cyclase. Using electrophoretic mobility shift assays and specific antibodies, we showed that CREB-1 binds specifically to the -79 to -52 region of the CD4 promoter. Last, we have identified two open reading frames (ORFs) of HHV-6, U86 and U89 from the immediate-early locus A, that can transactivate the CD4 promoter in HeLa cells. However, transactivation of the CD4 promoter by ORFs U86 and U89 is independent of the CRE element, suggesting that additional HHV-6 ORFs are likely to contribute to CD4 gene activation. Taken together, our results will help to understand the complex interactions occurring between HHV-6 and the CD4 promoter and provide additional information regarding the class of transcription factors involved in the control of CD4 gene expression.

* Corresponding author. Mailing address: Centre de Recherche du CHUL, Rheumatology and Immunology Dept., Room T1-49, 2705 Laurier Blvd., Sainte-Foy, Quebec, Canada G1V 4G2. Phone: (418) 654-2772. Fax: (418) 654-2765. E-mail: louis.flamand{at}crchul.ulaval.ca.

Journal of Virology, November 1998, p. 8797-8805, Vol. 72, No. 11
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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