The focus of the Virology Program is on performing basic mechanistic studies to determine how human oncogenic viruses induce cancer with the goal of developing new specific therapies and cutting edge approaches for vaccine development and gene therapy. The specific goals of the Virology Program are to develop effective new vaccines for viral infection and cancer and viral vectors for gene delivery, identify the effects of viral infection on innate immunity and inflammation, determine the mechanisms through which human tumor viruses cause cancer with a special focus on AIDS-associated virally induced cancers, and to utilize this knowledge to expand and develop experimental translational studies. To accomplish these goals, the effects of viruses on innate immunity and inflammation are being determined using alphaviruses and corona viruses as model systems, and identifying the effects of EBV and KSHV on interferon regulatory factors and toll-like receptors. The Immunology Program has made major discoveries on the mechanisms of the innate immune system including the discovery of NLR proteins that recognize pathogens to trigger the immune response. There are extensive ongoing collaborations between Drs. Jenny Ting, Mark Heise, and Bob Johnston to identify the mechanisms through which viruses inhibit this process.
The etiologic contributions of the human tumor viruses, EBV, KSHV, and HPV are being determined through the study of clinical samples, in vitro transformation systems, and animal models. Pathways essential for transformation have been identified and are under further study including activation of the PI3kinase/beta-catenin/TCF pathway by EBV and KSHV, activation of NFkB, and the role of DNA damage during viral replication. Additional research includes the biochemical characterization and electron microscopic visualization of the Epstein Barr Virus (EBV) and Kaposi Sarcoma-associated Herpesvirus (KSHV) transforming proteins, latent membrane protein 1 and K1, and the replication complex of herpes simplex virus (HSV), and EBV and KSHV protein kinases. The program will continue to dissect the viral/cellular molecular interactions that occur during viral infection and determine how specific molecular events contribute to viral pathogenesis and oncogenesis.
The overall goal of the Virology Program is to: Identify the mechanisms through which viruses contribute to cancer with the intention of developing unique and specific therapies to cure or eliminate these cancers. To achieve this goal, the Program has four major programmatic themes: Immunity, Pathogenesis, Virus:Cell Interactions, and AIDS-associated cancers. Members of the Virology Program have research projects in all of these programmatic areas:
Members of the Virology Program study mechanisms to improve vaccine development and characterize effects on innate and acquired immunity. Viral vaccination is one of the greatest successes in modern medicine and the development of new vectors for vaccination of viruses linked to cancer and against tumor-specific proteins may provide new ways to prevent and treat cancer.
The innate immune response is an important factor in controlling and determining the outcome of viral infections. Hence, this pathway is targeted in multiple ways by many viruses. Cytoplasmic sensors such as RIG-I or MDA5 can bind to single stranded or double stranded RNA leading to activation of kinases that phosphorylate IRF3 to induce its dimerization and nuclear translocation and subsequent induction of interferon (IFN). This pathway can also activate NFkB to activate IFN. IFN activation results in activation of the STAT signaling pathway that induces antiviral genes. Toll like receptors can also recognize viral nucleic acids leading to the activation of NFkB and IRF7. The many levels of regulation of these pathways are targeted in unique ways by viral proteins and investigators within the Virology Program will continue to identify the specific points where viral proteins interact with cellular proteins to block function and impair the immune response.
- Viral Pathogenesis
Viral pathogenesis is explored through several mechanisms by the Virology Program. Clinical samples of human cancers that are associated with specific viruses are used for detailed molecular analyses. The effects of viruses on cellular expression have been assessed using microarrays, viral/cellular interacting proteins have been identified using proteomics, and genetic changes within the tumors have been identified. Members of the Virology program also have developed animal models that mirror the virally induced tumors. These systems and the further study of human tumor samples that can be serially passaged as xenografts in immunocompromised mice will facilitate testing of specific inhibitors to impair tumor development.
- Viral:Cell Interactions
Cellular regulatory pathways that are critical to malignant growth and their key molecular properties have in many cases been identified through the study of the interaction of viral and cellular proteins. The tumor suppressor p53 was identified through its interaction with SV40 T antigen and subsequent studies revealed its suppressive effects on cell cycle progression and its enhancement of apoptosis. Similarly, the HPV oncoprotein E6 was shown to interact with a protein designated E6AP, which was subsequently shown to be a ubiquitin ligase. This was one of the first revelations of the power of ubiquitination in the regulation of protein stability and location. The ubiquitin system is now known to be one of the central regulators of normal cellular function that is affected by HPV and other tumor viruses, including EBV, in the process of cell transformation. Additional ongoing studies by members of the Virology Program have identified viral specific activation of essential cell signaling pathways and identified novel viral effects on cell growth properties that are essential for viral effects on cell growth and have identified specific interactions that are required for these effects.
- AIDS-Associated Malignancies
An increasingly important clinical problem in AIDS is the development of multiple types of cancer. These cancers account for most of AIDS-associated mortality both in the US as well as in developing nations. Like most AIDS associated pathologies, the AIDS-associated cancers result from immunosuppression, and as such most of the AID-associated cancers are caused by viral infection. The first major AIDS-defining cancer was Kaposi's sarcoma which is the leading cancer that develops in the HIV-positive population in the U.S. and worldwide. Peripheral and central nervous system lymphomas caused by EBV are also a major source of mortality. More recent studies have revealed increased numbers of HPV-associated cervical and anal cancer. With this in mind, Drs. Raab-Traub and Earp recruited Drs. Damania and Webster-Cyriaque in 2000, and Dr. Dittmer in 2004, as faculty members of LCCC.
The Lineberger Cancer Center has recently created a new focus group led by Dr. Damania on AIDS-associated malignancies to study both traditional AIDS-defining viral cancers as well as the emerging AIDS-associated non-viral cancers. Studies within the program will characterize the cancers that develop in AIDS and determine factors that contribute to this development. Transmission, strain variation, immune response, and cell growth and activation will be evaluated with the goal to increase translational studies.
The Program is led by Dr. Nancy Raab-Traub, a Sarah Graham Kenan Professor, who is an internationally recognized leader in the study of the molecular pathogenesis of EBV infections and EBV associated cancers.