Inhibition of replication and transcription activator and latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus by morpholino oligomers.

TitleInhibition of replication and transcription activator and latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus by morpholino oligomers.
Publication TypeJournal Article
Year of Publication2007
AuthorsZhang Y-J, Wang K-Y, Stein DA, Patel D, Watkins R, Moulton HM, Iversen PL, Matson DO
JournalAntiviral research
Volume73
Issue1
Pagination12-23
Date Published2007 Jan
ISSN0166-3542
KeywordsAntigens, Viral, Base Sequence, Cell Line, Tumor, DNA Replication, Gene Expression Regulation, Viral, Herpesvirus 8, Human, Humans, Immediate-Early Proteins, Molecular Sequence Data, Morpholines, Morpholinos, Nuclear Proteins, Trans-Activators, Viral Proteins, Virus Latency, Virus Replication
Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV) is associated with Kaposi's sarcoma and primary effusion lymphoma (PEL). The KSHV replication and transcription activator (RTA) and latency-associated nuclear antigen (LANA) play key roles in activating KSHV lytic replication and maintaining KSHV latency, respectively. Phosphorodiamidate morpholino oligomers (PMO) are similar to short single-stranded DNA oligomers, but possess a modified backbone that confers highly specific binding and resistance to nucleases. In this study, RTA and LANA mRNA in PEL cells were targeted by antisense peptide-conjugated PMO (P-PMO) in an effort to suppress KSHV replication. Highly efficient P-PMO uptake by PEL cells was observed. Treatment of PEL cells with a RTA P-PMO (RP1) reduced RTA expression in a dose-dependent and sequence-specific manner, and also caused a significant decrease in several KSHV early and late gene products, including vIL-6, vIRF-1, and ORF-K8.1A. KSHV viral DNA levels were reduced both in cells and culture supernatants of RP1 P-PMO-treated cells, indicating that KSHV lytic replication was suppressed. Treatment of BCBL-1 cells with P-PMO against LANA resulted in a reduction of LANA expression. Cell viability assays detected no cytotoxicity from P-PMO alone, within the concentration range used for the experiments in this study. These results suggest that RP1 P-PMO can specifically block KSHV replication, and further study is warranted.

DOI10.1016/j.antiviral.2006.05.017
Alternate JournalAntiviral Res.