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An NCI-designated Comprehensive Cancer Center, affiliated with the University of Pittsburgh School of Medicine
Research
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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.
Dr. Mellors' laboratory focuses on resistance to antiretroviral drugs used for treatment and HIV prevention and on mechanisms of HIV persistence and strategies to deplete the reservoirs that are the barrier to curing HIV infection. His work on HIV reservoirs showed that low-level viremia persists in most individuals on long-term suppressive ART, and that the level of residual viremia is predicted by the level of viremia before ART. Current work focuses on identifying agents to reverse HIV latency and to eliminate HIV infected cells. The impact of innovative therapies on HIV reservoirs is being studied in Phase I/II trials of histone deacetylase inhibitors, monoclonal antibodies to immune checkpoint ligands, monoclonal antibodies to HIV envelope glycoproteins, and TLR agonists.
Dr. Moore focuses his research on the link between viruses and cancer. Through his research, he hopes to answer why some viruses evolve to cause cancer while others cause nothing worse than the common cold. Dr. Moore and his wife, Yuan Chang, MD, discovered Kaposi’s sarcoma-associated herpesvirus (KSHV), also called human herpesvirus 8. KSHV causes Kaposi’s sarcoma, the most common malignancy occurring in AIDS patients. Kaposi’s sarcoma, a disease in which cancer cells are found in the tissues under the skin or mucous membranes, can be very aggressive in people whose immune systems are suppressed. Prior to this discovery, scientists had worked for 20 years to find an infectious agent associated with Kaposi’s sarcoma. He and Dr. Chang also are the discoverers of Merkel cell polyomavirus, which is the culprit that causes the rare and deadly skin cancer, Merkel cell carcinoma.
Innate immunity of an organism is the inborn protection against invading pathogens. We are interested in the host innate immune response during virus infection and cancer. Although several basic principles of virus detection and host signaling have been identified, the specific mechanisms by which these pathways are modulated by host components during microbial infection or tumor progression remains poorly understood. Following are some of the specific research topic we are interested:
The Shair Lab studies the human tumor virus “Epstein-Barr virus,” a ubiquitous herpesvirus with 90-95% seropositivity among adults worldwide. The resulting chronic infection can lead to EBV-associated cancer, which can occur in the immune-competent, and the immune-compromised such as post-transplant patients and HIV+ patients. A major focus is to translate these molecular studies to benefit cancer risk assessment and to elucidate EBV molecular pathogenesis in EBV-associated B-cell lymphomas and epithelial cell cancers. One EBV-associated cancer we study is nasopharyngeal carcinoma (NPC), a cancer with high prevalence in specific ethnic populations such as Alaskan Inuits and Southeast Asians. Our projects apply principles in molecular virology, epidemiology, and cell biology. One unique resource at our disposal is a biobank of primary nasopharyngeal cells that we built at the UPMC Hillman Cancer Center. These samples are used to address questions regarding the cellular response to EBV infection in the nasopharyngeal epithelium using techniques such as 3-D cell culture, single cell RNA-sequencing, and microscopy. Furthermore, by studying the molecular signature of the cellular humoral response to EBV antigens, we have profiled the antibody repertoire in persons known to be at risk of developing NPC. This information can be used to develop a risk assessment assay for NPC. We are a highly collaborative team of diverse scientists that tackle questions in molecular virology using interdisciplinary science.
Studies on animal polyomaviruses have provided a wealth of information for cancer biology. Research on the simian and murine polyomaviruses (SV40 and PyV) led to the discovery of tumor suppressor proteins p53 and retinoblastoma (pRb) and unveiled the importance of tyrosine kinase activities in tumorigenic signaling. Our research exploits the human Merkel cell polyomavirus (MCV) that causes most Merkel cell carcinoma (MCC), a rare but deadly skin cancer that exhibits similarity to the tactile sensor “Merkel cells”. Despite the rarity of MCC, MCV infection is common, and nearly all healthy adults were asymptomatically infected and shed MCV from their skin. MCV is a small circular DNA virus that persists in currently unidentified dermal cells. There are two accidental events that are essential for MCV tumorigenesis and act as triggers that turn this common virus into a cancer-causing virus: insertion of linearized viral DNA into host cellular genome and introduction of a specific mutation that inactivates the viral replication enzyme.
By using molecular and cell biological approaches, our lab investigates: (1) MCV lifecycle processes, especially viral DNA replication, gene expression, and viral progeny production (2) MCV target cells wherein MCV persists or transforms into MCC, (3) biological triggers that disrupt the circular MCV DNA and facilitate insertion into host genome, and (4) critical cellular signaling activated by MCV proteins that promote MCC carcinogenesis. A full understanding of these events will help us prevent MCV-associated MCC, as well as identify therapeutic strategies for this deadly cancer.
1. Biomarkers of neuroinflammation: Using positron emission tomography (PET), we have recently imaged macrophage activation in human and non-human primate models of neurological disease. Using a novel radioligand (PK11195) to assess activated microglia in brains of living HIV-infected human and SIV-infected primates, these studies demonstrated the feasibility, but limited sensitivity of PK11195 PET in monitoring central nervous system (CNS) inflammation (Venneti et al., 2008; Venneti et al., 2004; Venneti et al., 2009; Wiley et al., 2009). While performing these PET studies, we took advantage of the study's serial time points to discover biomarkers of neuroinflammation in serum and cerebrospinal fluid. Using unbiased proteomic analysis with SELDI-TOF mass spectrometry, we discovered a highly sensitive and reproducible biomarker of CNS inflammation, chitinase 3-like 1 protein (CHI3L1). We and other groups have since observed expression of CHI3L1 in a broad spectrum of CNS inflammatory diseases (Bonneh-Barkay et al., 2010). 2. Control of neuroinflammation: While of great utility as a biomarker, CHI3L1 is becoming even more important as a member of a new class of proteins mechanistically involved in the control of neuroinflammation. These novel proteins modulate the interaction between inflammatory cells and CNS extracellular matrix. Using transgenic mice where the mouse homolog of CHI3L1 was deleted by homologous recombination, we have examined the role of this protein in animal models of multiple sclerosis (EAE) and traumatic brain injury (Bonneh-Barkay et al., 2012). In both models, deletion of CHI3L1 led to worse clinical and pathological outcome. Current studies in our lab are aimed at elucidating the molecular mechanism by which CHI3L1 limits inflammation and how to mimic its action using small molecules. These studies hold the potential of developing novel therapies to decrease neuroinflammation, potentially supplementing or synergistically interacting with current anti-inflammatories. 3. Age-related neurodegeneration: While intuitively obvious, it warrants remembering that the single most important determinant of neurodegeneration is age. Through extensive collaborations with the Alzheimer's Disease Research Center, we clinically document the neuropathology of AD and related diseases. The beta amyloid hypothesis of AD proposes that toxic fragments or oligomers of beta amyloid mediate neurodegeneration. We and others have explored the capacity of active immunization to eliminate beta amyloid from the aging primate brain (Kofler et al., 2012). Current studies in the lab are examining how lentiviral infection and combined anti-retroviral therapy modulate age related neurological processes and gene expression associated with neurodegeneration. 4. Viral encephalitis: Collaborations with other University of Pittsburgh investigators have allowed us to expand our studies of the brain's susceptibility to viral infections. Our research team has discovered the heightened susceptibility of the brain to aerosol transmission of common viral pathogens. Arboviruses that normally infect through insect vectors cause limited systemic disease, but when delivered through aerosol route, they rapidly cause lethal encephalitis. How the brain's innate immune response and systemic adaptive immunity protect the CNS is a current focus of the lab. We have discovered that host exposure to seasonal influenza determines susceptibility to lethal avian influenza. Newly proposed studies will elucidate the role of innate and adaptive immunity in conferring this protection. Importantly, from a public health perspective, this team is also researching how immunization protects or predisposes to encephalitis.
