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Research Articles: Therapeutics, Targets, and Development

Blockade of viral interleukin-6 expression of Kaposi's sarcoma–associated herpesvirus

¹ Molecular Virology Laboratory, VA-MD Regional College of Veterinary Medicine, University of Maryland, College Park, Maryland and ² AVI BioPharma, Inc., Corvallis, Oregon

Requests for reprints: Yan-Jin Zhang, Molecular Virology Laboratory, VA-MD Regional College of Veterinary Medicine, University of Maryland, 8075 Greenmead Drive, College Park, MD 20742. Phone: 301-314-6596; Fax: 301-314-6855. E-mail: zhangyj{at}umd.edu

Abstract

Kaposi's sarcoma–associated herpesvirus (KSHV), also known as human herpesvirus 8, is associated with several malignant disorders, including Kaposi's sarcoma, primary effusion lymphoma (PEL), and multicentric Castleman's disease. An early lytic gene of KSHV encodes viral interleukin-6 (vIL-6), a viral homologue of the proinflammatory cytokine and an autocrine/paracrine growth factor human IL-6. In this study, we examined the effects of suppressing vIL-6 expression in PEL cells with antisense peptide-conjugated phosphorodiamidate morpholino oligomers (PPMO). PPMO are ssDNA-analogues that have a modified backbone and enter cells readily. Treatment of PEL cells with a PPMO designed against vIL-6 mRNA led to a marked reduction in the proportion of vIL-6-positive cells detected by immunofluorescence assay. Analysis by Western blot confirmed a specific reduction in the vIL-6 protein level and showed that the reduction was dependent on the dose of vIL-6 PPMO. PEL cells treated with the vIL-6 PPMO exhibited reduced levels of cellular growth, IL-6 expression and KSHV DNA, and an elevated level of p21 protein. Treatment of PEL cells with a combination of two vIL-6 PPMO compounds targeting different sequences in the vIL-6 mRNA led to an inhibitory effect that was greater than that achieved with either PPMO alone. These results show that PPMO targeting vIL-6 mRNA can potently reduce vIL-6 protein translation and indicate that further exploration of these compounds in an animal model for potential clinical application is warranted. [Mol Cancer Ther 2008;7(3):712–20]

Grant support: National Cancer Institute, NIH, USPHS grant CA-103612 (Y-J. Zhang).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: Current address for R.S. Bonaparte: 7 East 36th Street, Richmond, VA 23224.

Received 9/ 5/07; revised 11/ 9/07; accepted 12/ 5/07.