Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV or HHV-8) are two human pathogens which are etiologically linked with a number of malignancies such as lymphomas, nasopharyngeal carcinoma and Kaposi’s sarcoma. As such, they are also called tumor-associated herpesviruses. However, studies on EBV and KSHV have been hampered by the lack of efficient de novo infection systems and suitable small animal models. Murine gammaherpesvirus-68 (MHV-68 or γHV-68), a member of the gammaherpesvirus family, is phylogenetically related to EBV and KSHV. MHV-68 has emerged as a model to study its human counterparts in recent years, because it replicates robustly in permissive cell lines, generates progeny viruses to high titers and is able to infect laboratory mice.
All herpesviruses have two distinct life cycles, latency and lytic replication. The switch from latency to lytic replication for KSHV and MHV-68 is controlled by a virally-encoded immediate-early protein, Replication and Transcription Activator (RTA), which is conserved among all gammaherpesviruses. Previous studies have demonstrated that RTA proteins of Epstein-Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV) can activate the promoter of many viral early lytic genes through direct or indirect mechanisms. However, in MHV-68, the mechanism of the interaction between RTA and viral promoters had not been characterized. Dr. DENG Hongyu’s group at the Institute of Biophysics, Chinese Academy of Sciences identified two RTA-responsive elements (RREs) for MHV-68, named RREA and RREB.
They further demonstrated that RTA directly binds to these two RREs both in vitro and in vivo, and characterized the nucleotides important for mediating binding by RTA. Moreover, they have verified the functional significance of RREs in the context of viral genome and shown that RREB is responsible for mediating RTA activation of ORF18 transcription during viral infection.
This is the first time that RTA binding sites in MHV-68 have been identified. Furthermore, since ORF18 was the first identified trans-factor encoded by a gammaherpesvirus that regulates viral late gene expression, their study has also contributed to the delineation of the expression cascade of gammaherpesviral lytic genes: RTA as an immediate-early gene activates the expression of ORF18, an early gene, then ORF18 in turn activates the expression of viral late genes encoding structural proteins such as ORF26 and ORF65.
This study is published recently on Journal of Virology (2011 Nov; 85(21):11338-50; Epub 2011 Aug 17).
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