Samuel H. Speck

Reactivation of Epstein-Barr virus: regulation and function of the BZLF1 gene

The switch from latent infection to virus replication in Epstein-Barr virus (EBV)-infected B cells is initiated by expression of the viral BZLF1 gene. Recent studies have identified the key cellular transcription factors involved in regulating this switch in viral programs and the signal transduction pathways to which they respond. Understanding this switch may facilitate development of strategies to interfere with EBV infection.

Cyclosporin A-sensitive induction of the Epstein-Barr virus lytic switch is mediated via a novel pathway involving a MEF2 family member

Induction of the Epstein‐Barr virus (EBV) lytic cycle by crosslinking surface immunoglobulin is inhibited by the immunosuppressants cyclosporin A (CsA) and FK506. This correlates with the ability of CsA to inhibit Ca2+‐dependent transcription of the lytic cycle switch gene BZLF1. It is shown here that CsA sensitivity maps to three sites (ZIA, ZIB and ZID) that bind the serum response factor‐related protein MEF2D. A synthetic promoter containing multiple copies of a MEF2D site from Zp, in conjunction with a CREB/AP‐1 site (ZII) from Zp, exhibits CsA‐sensitive inducibility. Furthermore, the Zp MEF2D sites were functionally interchangable with MEF2 sites derived from heterologous promoters. While no evidence of a NFAT family member binding to either the MEF2 or CREB/AP‐1 sites was obtained, it could be demonstrated that CsA‐sensitive induction of Zp was mediated by calcineurin and NFATc2 in synergy with either phorbol ester or especially with the EBV‐induced Ca2+/calmodulin‐dependent kinase type IV/Gr. These studies identify Zp as prototypic of a novel class of CsA‐sensitive and NFAT‐dependent promoters defined by the presence of MEF2 sites.

Host and viral genetics of chronic infection: a mouse model of gamma-herpesvirus pathogenesis

A general association of human and primate lymphotropic herpesviruses (gamma-herpesviruses) with the development of lymphomas, as well as other tumors, especially in immunocompromised hosts, has been well documented. The lack of relevant small animal models for human gamma-herpesviruses has impeded progress in understanding the role of these viruses in the development of chronic disease. Recent research characterizing infection of inbred strains of mice with a murine gamma-herpesvirus, gamma-herpesvirus 68 (gammaHV68), is providing insights into viral and host factors involved in the establishment and control of chronic gamma-herpesvirus infection.