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Viral Oncology investigators

Moses Bility, PhD
2136 Parran Hall
130 DeSoto Street
Pittsburgh PA
Phone: 412-648-8058
Research Interests and Keywords:
  • Hepatitis
  • HIV
  • HCV
  • HBV
  • liver disease
  • innate immunity
  • inflammation
  • macrophage activation
  • humanized mouse models
Over 500 million people worldwide are infected with chronic liver pathogens including chronic hepatitis viruses and zoonotic liver flukes, which leads to severe liver diseases. Additionally, several studies have demonstrated that HIV co-infection exacerbate chronic HBV/HCV-induced liver diseases, resulting in increased mortality. The increased prevalence of obesity and metabolic syndrome-associated non-alcoholic fatty liver disease in the United States and other developed countries also contributes to the global liver disease burden, with approximately 25% of the US population affected. The development of therapeutics against these diseases has been hindered by the lack of robust small animal models that accurately recapitulates human disease; in most cases rodents are not susceptible to infections or are resistant to disease. The lack of robust small animal models of human infectious diseases also poses a major hindrance in studying emerging diseases such as Zika virus. Innate immune cell infiltration including macrophage infiltration is a major component of the inflammatory milieu associated with chronic liver infections, non-alcoholic steatohepatitis and most human infections. Importantly, macrophages play a critical role in innate immune response, modulating gut microbiota, macronutrients (i.e., iron, lipids, etc.) sensing and metabolism, and tissue integrity/remodeling; therefore, elucidating the role of macrophage activation in human infectious diseases and metabolic syndrome-associated diseases will provide novel insight into the mechanisms of immune dysregulation and tissue pathogenesis. The Bility lab is broadly interested in elucidating the role of macrophage polarization in human infectious diseases and obesity/metabolic syndrome-associated diseases utilizing humanized mouse models carrying autologous functional human immune system, human liver cells and other human organ systems along with strong emphasis on collaborative translational research with clinical investigators. Major research efforts are: 1) Elucidating the role of macrophage polarization in chronic liver infections (HBV, HCV, liver fluke), HIV-hepatitis virus co-infections and associated liver diseases; 2) Elucidating the nexus between macrophage polarization and gut microbiota in fatty diet-induced non-alcoholic steatohepatitis and associated liver diseases; 3) Developing humanized mouse model for human diseases, including viral hepatitis, HIV, arbovirus, etc. In addition to his biomedical research, Dr. Bility also has strong interests in health security and pandemic/disaster response and management. Dr. Bility has extensive training and expertise in medical planning and operations for various contingencies including pandemic, chemical, biological, radiological, and nuclear (CBRN) disaster events in both domestic and international conditions.
James Conway
Shou-Jiang Gao, PhD
G.17A Hillman Cancer Center Research Pavilion
Angela Gronenborn, PhD
1050 BST 3
Pittsburgh PA
Phone: 412-648-9959
Research Interests and Keywords:
  • Structural biology
  • gene regulation
  • HIV pathogenesis
  • macromolecules
  • nuclear magnetic resonance spectroscopy
  • NMR
  • protein folding

Research in my lab combines nuclear magnetic resonance (NMR) spectroscopy with biophysics, biochemistry, and chemistry to investigate cellular processes at the molecular and atomic levels in relation to human disease. We presently focus on two areas in biology: gene regulation and HIV pathogenesis. To understand how biological macromolecules work and intervene with respect to activity and function, detailed knowledge of their architecture and dynamic features is required. Evaluation of the major determinants for stability and conformational specificity of normal and disease-causing forms of these molecules will allow us to unravel the complex processes associated with disease. Our group has developed new NMR methods for determining three-dimensional structures of biological macromolecules and applies these to challenging systems. Key contributions include the development of restrained molecular dynamics/simulated annealing algorithms and multidimensional, heteronuclear spectroscopy, which allowed the extension of conventional NMR methods to higher molecular weight systems. Our group has solved solution structures of a large number of medically and biologically important proteins, including cytokines and chemokines, transcription factors and their complexes and various HIV and AIDS related proteins. Work is also carried out on protein folding and design using the model protein GB1.

Fred Homa, PhD
515 Bridgeside Point II
450 Technology Drive
Pittsburgh PA
Phone: 412-648-8788
Research Interests and Keywords:
  • Herpes simplex virus type 1 (HSV-1)
  • capsid assembly
  • DNA packaging
Dr. Homa's research is focused on understanding the molecular basis of herpes simplex virus type 1 (HSV-1) capsid assembly and viral genome packaging into the viral capsid. DNA encapsidation and cleavage involves the coordinated interaction of several HSV proteins that are essential for production of infectious virions. How these multi-protein assemblies associate and interact to accomplish this complex task touches on fundamental questions in biology. The HSV-1 genome is translocated into the icosahedral procapsid through a donut-shaped 'portal' that is present at one of the 12 vertices of the procapsid. This process is directed by the terminase complex, which consists of the HSV UL15, UL28, and UL33 proteins that function both as part of the ATP-hydrolyzing pump which drives DNA into the capsid, and also as a nuclease that cuts the concatemeric DNA at specific sites to yield a capsid containing the intact genome. The capsid is then stabilized by the addition of the capsid vertex specific component (CVSC), composed of the UL17 and UL25 proteins, which functions to retain the packaged DNA and to signal for nuclear egress of the mature DNA-filled capsid, as well as for nuclear attachment of the incoming, infecting capsid. Seven viral gene products are required for the stable packaging of viral DNA into the preformed HSV procapsid. Orthologs of these HSV DNA packaging genes are found in all three classes (alpha, beta, and gamma) of herpesviruses. Information obtained about the function of these proteins from these studies should therefore apply to other herpesviruses such as human cytomegalovirus, varicella zoster virus and Epstein-Barr virus.
Patrick Moore, MD, MPH
Hillman Cancer Center
Lab 1.8
Pittsburgh PA
Research Interests and Keywords:
  • Human tumor virology (KSHV, MCV and digital transcriptome subtraction)
Saumendra Sarkar, PhD
Hillman Cancer Center
Lab 1.7 5117 Centre Avenue
Pittsburgh PA
Research Interests and Keywords:
  • RIG-I-like receptors (RLR)
  • interferon (IFN)-stimulated genes
  • toll-like receptor 3 (TLR3)
  • innate immune signaling
  • anti-viral innate immunity
  • type I IFN; IFN signaling
  • IFN regulatory factor 3 (IRF3)
  • tumor microenvironment

Innate immunity of an organism is the inborn protection against invading pathogens. Because it is inborn, and entrusted with the protection of the host from a vast array of previously unknown invaders, the innate immune system generates a generalized alert response upon pathogen detection. This alert is chemically mediated by a class of molecules called cytokines, such as interferons. A critical task for this host protection system is to distinguish foreign or non-self, from self, and initiate their destruction or containment. The sensors or the receptors of the innate immune system accomplish this by recognizing specific molecular patterns, which are common to pathogens or pathogen associated molecules, but absent in the host. We focus on a particular subset of these sensors/receptors, which are involved in sensing virus infection. In order to protect the host from viral invasion, the innate immune system has evolved sensors to detect foreign nucleic acids. Several unique features of virally produced DNA or RNA are exploited to distinguish viral nucleic acids from that of the host. One such unique nucleic acid is double-stranded RNA (dsRNA) ' a common byproduct or intermediate in viral genome replication. In mammals, receptors like toll-like receptor 3 (TLR3), retinoic acid-inducible gene I (RIG-I), and melanoma differentiation-associated gene 5 (MDA5) are the three known sensors of dsRNA. Single-stranded viral RNA is sensed by toll-like receptors 7 and 8 (TLR7 and TLR8), while viral DNA is detected by toll-like receptor 9 (TLR9) and other cytoplasmic receptors. We study two related aspects of the signaling process involved in interferon production in the context of infectious disease and cancer: 1) modulation of viral RNA sensing mechanisms; and 2) alternative mechanisms of interferon induction in specific tumors.

Masahiro Shuda
UPCI Research Pavilion at Hillman Cancer Center, 1.9
5117 Centre Avenue
Pittsburgh PA
Phone: 412-623-7733
Gutian Xiao, PhD
Hillman Cancer Center
Lab 1.19A 5117 Centre Avenue
Pittsburgh PA
Research Interests and Keywords:
  • Signal transduction in immunity and tumorigenesis
Yuan Chang, MD
Hillman Cancer Center
5117 Centre Ave Suite 1.8
Pittsburgh PA
Research Interests and Keywords:
  • Tumor viruses
  • Kaposi's sarcoma associated herpesvirus (KSHV)
  • Merkel cell polyomavirus (MCV)
  • digital transcriptome subtraction
  • tumor virus discovery

The work of our group (jointly directed by Patrick Moore and Yuan Chang) has focused on human tumor viruses since the early 1990s when we identified Kaposi's sarcoma associated herpesvirus (KSHV/HHV8) and showed that this virus was causally associated with Kaposi's sarcoma, the most common AIDS-related cancer in the United States and the most common malignancy in parts of Africa. We sequenced the KSHV genome, developed serologic assays, determined its prevalence in human populations, and characterized many of its critical viral oncoproteins. We have continued to study virus-host cell interactions in the context of dysregulation of pro-proliferative and anti-apoptotic pathways. We recently identified the seventh human tumor virus, Merkel cell polyomavirus (MCV), from a Merkel cell carcinoma (MCC). We characterized the transcriptional products of MCV and described the early region viral T antigen oncoproteins. Our work has established that MCV causes ~80% of MCC: we determined that the virus is clonally integrated in MCC tumor cells; that human tumor-associated Large T (LT) antigens contain signature truncation mutations; that T antigen proteins are expressed in MCC tumor cells by novel antibodies we developed; and we are the first laboratory to show rodent cell transformation by MCV sT antigen but not the LT antigen. We have identified several novel cellular interactors for MCV T antigens that open new avenues of investigating critical oncogenic signaling pathways. We have focused on many aspects of cancer etiology as modeled through oncogenic tumor viruses.

Neal DeLuca, PhD
514 Bridgeside Point II
450 Technology Drive
Pittsburgh PA
Research Interests and Keywords:
  • HSV-1-mediated regulation of gene expression
Andrea Gambotto, MD
300 Technology Drive
Pittsburgh PA
Research Interests and Keywords:
  • Development of adenoviral vector based vaccines for HIV-1 and influenza
Joseph Glorioso, PhD
450 Technology Drive
Suite 300
Pittsburgh PA
Research Interests and Keywords:
  • HSV vectors, glioblastoma, chronic pain

Dr. Glorioso has spent his career studying the molecular biology of HSV and the last 20 years developing HSV gene vectors. He is a world-wide leader in this field and has to the expertise to develop the technology related to the treatment of diseases of the peripheral and central nervous system. His interest in peripheral nerve disease has included nerve degeneration due to diabetes and cancer drug therapies that have led to treatments of animal models. Studies to understand the pathophysiology of chronic pain and the identification of gene therapy interventions that create effective pain therapies have been long standing interests and he was among the first to develop HSV vectors to treat pain. This research has culminated in clinical trials for treatment of cancer pain. Dr. Glorioso has also focused his attention on neurodegenerative diseases that include SCA1 and Huntington's disease and the development of oncolytic vectors to treat brain tumors. Part of this research extends his application of HSV vectors for vector delivery across the blood brain barrier and for targeting specific neuronal cell populations in animals. He has also recently developed HSV vectors for the creation and neuronal differentiation of human iPS cells derived from fetal brain and human fibroblasts.

Paul Kinchington, PhD
Eye and Ear Institute
203 Lothrop Street, Room 1016
Pittsburgh PA
Phone: 412-647-6590
Research Interests and Keywords:
  • HSV
  • VZV
  • herpes simplex virus
  • zoster
  • varicella
  • viral infection
  • viral latency
  • infectious eye disease
  • pain and post-herpetic neuralgia
  • neuronal infection
Dr. Kinchington's research program addresses the biology of two human alpha-herpesviruses (VZV and HSV) and their interaction with neurons in model systems. Both infect most of the human population, and have developed means to persist in the host sensory neurons, only to later reactivate and cause further disease that leads to significant human morbidity. Work is primarily focused on varicella-zoster virus (VZV), which causes chickenpox upon primary infection and the debilitating herpes zoster ("shingles") when the virus reactivates from latency. Zoster develops on a third of those infected with VZV, and most cases are painful. However, 30% develop long-term, intractable and debilitating chronic pain (post-herpetic neuralgia, or PHN) which is difficult to treat. Many neurological diseases, paralyses and brain infarctions are caused by VZV, and neurological problems may affect vision and cause blindness, such as stromal and retinal diseases, inflammation and ophthalmoplegia. Our work addresses two aspects of VZV. One addresses a model of VZV-induced pain in the rat, as a model of PHN. The model is not only used to address how VZV induces pain, but also to test new strategies for pain alleviation. A second VZV research program is using an in vitro model of VZV-human neuron interactions to address axonal transport and latency. The model uses human neurons derived in vitro from human stem cells and progenitors. We also study herpes simplex virus type 1 (HSV-1), which may repeatedly reactivate from latency and cause problematic recurrent diseases, such as blinding stromal keratitis. Using an HSV-1 mouse ocular infection model, we are seeking to evaluate and augment the blocking of reactivation of HSV-1 by the cellular immune response at the sensory nerve ganglion. Currently, we are determining the parameters required to modulate and improve the function, number and effectiveness of CD8 T cells that infiltrate the latently infected ganglia. This includes determining those viral proteins that are targeted by cellular immunity, and the factors governing HSV targets of immunodominance.
John Mellors, MD
James Pipas, PhD
559B Crawford Hall
4249 Fifth Avenue
Pittsburgh PA
Phone: 412-624-4691
Research Interests and Keywords:
  • Simian virus 40 (SV40)
  • T antigen
  • tumorigenesis
Simian virus 40 (SV40) belongs to a small collection of viruses that induce tumors. We utilize SV40 as a model system for understanding the molecular events that drive tumorigenesis. Our studies focus on the virus-encoded master regulatory protein, large T antigen. Large T antigen controls several aspects of viral infection including DNA replication, transcription and virion assembly. In addition, T antigen is necessary and, in most cases, sufficient for SV40-mediated tumorigenesis. T antigen induces tumors in rodents and the neoplastic transformation of cells in culture by binding to key cellular proteins that regulate proliferation and survival, and altering their activities. Our basic strategy is to use a combination of genetics and proteomics to identify cellular targets of T antigen and then to use molecular biology and mouse model approaches to understand how these actions contribute to tumorigenesis.
Kathy Shair, PhD
Thomas Smithgall, PhD
530 Bridgeside Point II
450 Technology Drive
Pittsburgh PA
Research Interests and Keywords:
  • Protein-tyrosine kinases
  • Src-family kinase
  • Abl
  • Fes
  • AML
  • CML
  • myeloma
  • HIV
  • AIDS
  • drug discovery
  • chemical biology
In theory, inhibition of undesirable enzymatic activity responsible for disease can be accomplished either directly at the active site or indirectly at a distance (allostery). Important examples of selective enzyme inhibition come from the field of protein-tyrosine kinases, an emerging therapeutic target class for cancer and infectious diseases. Virtually all clinically useful kinase inhibitors to date compete for ATP binding at the kinase domain active site. However, the high degree of protein kinase sequence and structural homology limits the development of highly selective ATP-competitive kinase inhibitors. Alternative drug discovery avenues include allosteric inhibitors that target structural features outside of the kinase domain active site that are unique to individual kinase subfamilies. Allosteric inhibitor mechanisms are likely to exhibit greater specificity for their intended kinase targets, and may also stabilize kinase domain conformations that promote the action of existing inhibitors targeting the active site. Based on these principles, we are actively engaged in a drug discovery campaign to find small molecules that enhance the natural allosteric mechanisms associated with kinase domain regulation. We have developed high-throughput screening approaches based on this concept to identify selective inhibitors for protein-tyrosine kinases of the non-receptor class, including members of the Src, Fes/Fps and Abl kinase families. Selective inhibitors emerging from these screens have promise for future development in the treatment of several forms of leukemia, multiple myeloma, and HIV/AIDS.