I. George Miller John F. Enders Professor of Pediatrics; Professor of Epidemiology & Public Health and Molecular Biophysics & Biochemistry » Molecular Biophysics & Biochemistry » Microbiology » A.B. Harvard University 1958; M.D. Harvard Medical School 1962 Our research is directed at understanding a central unexplained phenomenon in virology, namely mechanisms underlying viral persistence and reactivation. We study two related human tumor viruses: Epstein-Barr virus (EBV), which is associated with Burkitt's lymphoma, nasopharyngeal carcinoma, and diffuse lymphoma in immunodeficient patients; and Kaposi's sarcoma-associated herpesvirus (KSHV), which is associated with Kaposi's sarcoma and lymphomas in body cavities that occur in patients with AIDS. Both viruses establish "latent states" in host cells, during which only a limited number of viral genes are expressed. We have shown that a single viral protein, ZEBRA, a transcriptional activator, is sufficient to disrupt EBV latency and to drive the lytic viral cycle to completion. ZEBRA interacts with another EBV protein, the R transactivator (Rta) to induce expression of viral early lytic cycle genes. A ZEBRA mutant that does not disrupt latency can be rescued by supplying Rta in trans. Our lab is studying the control of ZEBRA and Rta expression and their mechanisms of action and interaction. KSHV encodes a homologue of Rta in open reading frame 50. We have found that KSHV ORF 50 protein can activate expression of KSHV-encoded early lytic cycle genes such as a virally encoded cytokine, IL-6, an abundant non-coding nuclear polyadenylated RNA, and drive the KSHV lytic cycle to completion. We are studying the mechanism of action of KSHV ORF 50 protein and the function of viral IL6. We also investigate how the immune system regulates the latent and lytic cycle program of EBV in B cells. El-Guindy, A.S. and Miller, G. (2004). Phosphorylation of Epstein-Barr Virus ZEBRA protein at its casein kinase 2 sites mediates its ability to repress activation of a viral lytic cycle late gene by Rta. J. Virol. 78:7634-7644. Chang, P.J. and Miller, G. (2004). Autoregulation of DNA binding and protein stability of Kaposi's Sarcoma-associated herpesvirus ORF 50 protein. J. Virol. 78:10657-10672.