Regulation of Epstein-Barr virus lytic cycle activation in malignant and nonmalignant disease.

Like all other herpesviruses, the oncogenic human gammaherpesvirus, Epstein-Barr virus (EBV; human herpesvirus 4) manifests two distinct phases in its life cycle: latency and lytic replication. During latency EBV expresses a limited number of viral genes that are involved in tasks such as stimulating cell proliferation, inhibiting apoptosis, blocking viral lytic replication, and assuring accurate and equal partitioning of the episomal viral genome to daughter cells. Variants of the EBV latent life cycle, which are distinguished by the latent products expressed, are characteristic of each EBV-associated cancer. During the lytic replication phase of the EBV life cycle, many more viral genes, encoding enzymes, and other proteins involved in nucleotide biosynthesis, RNA processing, viral DNA replication, and capsid and viral envelope synthesis, are expressed. Two genes of EBV, BZLF1 and BRLF1, encode transcriptional activator proteins that mediate the switch between latency and the lytic cycle (1–3). Both genes are essential for this switch (4). BZLF1, encoding ZEBRA (Z, EB Replication Activator), is dominant in EBV (5), although the homologue of BRLF1, encoded in open reading frame (ORF) 50, is the dominant lytic switch protein in the related Kaposi’s sarcoma-associated herpesvirus (6). ZEBRA activates expression of Rta (R transactivator), the product of the EBV BRLF1 gene, in all cell backgrounds that have been studied. The capacity of Rta to activate ZEBRA expression is restricted to certain cell backgrounds (7,8). The molecular events involved in the switch between the latent and lytic replication phases of the EBV life cycle can be studied in cultured lymphoblastoid or lymphoma cell lines. Transfection of a ZEBRA expression vector is sufficient to activate the lytic cycle. A number of other exogenous stimuli are competent to trigger the switch; these include protein kinase C agonists such as phorbol esters, histone deacetylase inhibitors such as n-butyrate and Trichostatin A, anti-immunoglobulin, calcium ionophores, transforming growth factor-beta (TGF),