Molecular Pathogenesis of the Human Cancer Virus

Drs. Wang, Kieff, Kaye, Gewurz, and Zhao share common interests and are a leading group studying the molecular pathogenesis of the major human cancer viruses: Epstein Barr Virus (Wang, and Kieff, Gewurz, and Zhao), and Kaposi’s Sarcoma Herpes Virus (Kaye). An important general theme of their research is that these viruses over-activate cell growth and survival pathways, resulting in virus-infected cells being specifically susceptible to chemicals that only have lethal effects on cancer cells.

Drs. Wang, Kieff, Gewurz, & Zhao

Drs. Wang, Kieff, Gewurz, and Zhao’s groups study immune and biochemical mechanisms by which Epstein-Barr virus (EBV) causes lymphomas, Hodgkin’s disease, nasopharyngeal, and gastric cancers in humans. EBV-associated lymphomas and Hodgkin’s disease have a markedly accentuated prevalence in people who are immune-suppressed from HIV or other underlying immune suppressive disorders, including people on HAART, for whom EBV-associated lymphomas and Hodgkin’s disease remain the major cause of death. Studies of the mechanisms by which these viruses affect cell growth and survival have also revealed important aspects of normal and cancer growth. Through our collaborations with colleagues at HMS, Harvard, MIT, and the Broad Institute, we have access to state-of-the-art technologies for inhibitory compound screening and disruptive cell biology investigations. These include RNAi, vectored shRNA,gene knock-outs, as well as molecular genetics and proteomic approaches to characterize novel pathway components. High-throughput chemical screens have identified candidate latent membrane protein 1 (LMP1)/NF-kB inhibitors. In addition, CHiP-SEQ analyses have defined genome-wide binding sites for NF-kB transcription factor subunits (p50, p52, RelA, RelB, and cREL) in lymphoblastoid cells (LCLs). By leveraging the extensive Chip-Seq data sets generated in LCLs, Dr. Gewurz has developed new insights into how the NF-kB transcription factor subunits interact with one another, and in combination with other transcription factors to cause EBV associated cancers. Dr. Zhao is currently completing the first genomewide studies of nasopharyngeal cancer, a common EBV-associated malignancy, particularly in China and North Africa. These studies will likely enable more focused chemical approaches to NPC. Dr. Ben Gewurz uses RNAi and proteomic approaches to discover and characterize novel NF-kB pathway components, and high-throughput chemical screens to identify latent membrane protein 1 (LMP1)/NF-kB inhibitors. In addition, he uses CHiP-SEQ analysis to define the genome-wide binding sites for all five NF-kB transcription factor subunits (p50, p52, RelA, RelB, and cREL) in lymphoblastoid cells (LCLs). By leveraging the extensive Chip-Seq dataset generated in LCLs, he is developing new insights into how the NF-kB transcription factor subunits interact with one another, and in combination with other transcription factors.

Dr. Frederick Wang

Dr. Wang’s research studies of Epstein-Barr virus infection in cells, animal models, and in patients with nasopharyngeal cancer, to better understand and control this EBV-induced cancer, which is only initially responsive to current therapies. Dr. Wang also uses primate herpes viruses closely related to EBV in natural infection of New World or Old World nonhuman primates that have been identified, cloned, and sequenced, and the evolution of these related viruses provides unique insights into the molecular biology of this oncogenic herpes virus genus. Genetic systems for making mutant viruses are used to analyze viral gene function in cells, to determine how specific viral genes manipulate host cell gene expression, and to test their effects on viral pathogenesis in the context of organismal infection in non-human primates. Virus-specific immune responses important for control of EBV infection and associated malignancies are dissected from animal model systems and EBVinfected humans. Hypotheses for enhanced therapeutic strategies arising from a better understanding of viral pathogenesis and immune control are being formally tested in translational studies of virusspecific immunotherapy in patients with EBV-induced nasopharyngeal cancer.

Dr. Kenneth Kaye

Dr. Kaye’s group investigates the link between Kaposi’s sarcoma-associated herpesvirus (KSHV) or human herpesvirus 8 (HHV-8) and human malignancy. KSHV has a causative role in Kaposi’s sarcoma, primary effusion lymphoma, and multicentric Castleman’s disease, an aggressive lymphoproliferative disorder. The goal of his team is to gain a better understanding of the molecular mechanisms underlying KSHV pathogenesis. Dr. Kaye’s group is investigating the molecular mechanism of action of the KSHV protein, LANA, which is essential for virus survival and persistence in tumor cells.

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