|Institution||College of Medicine|
|Address||500 University Drive Hershey PA 17033|
Physician, Professor of Medicine (Infectious Diseases) and Microbiology & Immunology
Distinguished Educator, Penn State College of Medicine
OTHER CURRENT TITLES/ROLES:
Director, Antimicrobial Stewardship Program
President, Society of Distinguished Educators
Infectious Diseases Thread Leader for Medical Student Curriculum
Clinical Skills Instructor/Advisor in Waldhausen Society
SELECTED PAST TITLES/ROLES:
Vice-Chair, Biological Safety and Recombinant DNA Committee (1993 - 2011)
Chair, Hospital Infection Control Committee (1993 - 2011)
Faculty Organization Officer (Parliamentarian 2006-2010; President-Elect 2010-2011; President 2011-2013; Immediate Past-President 2013-2014)
Co-Director, Biological Basis of Disease First-Year Medical Student Course (2011-2013)
GRADUATE PROGRAM AFFILIATIONS:
Microbiology and Immunology, MD/PhD Degree Program, Biomedical Sciences (BMS) Graduate Program, Cell and Molecular Biology Graduate Program, Molecular Medicine Intercollege Graduate Program of the Huck Institutes of the Life Sciences
Postdoctoral Research Fellowship, Biochemistry and Medicine, Case Western Reserve University (1986-1989)
Fellowship, Infectious Diseases, University Hospitals of Cleveland and Cleveland Veterans Administration Hospital (1984-1989)
Residency, Internal Medicine, University Hospitals of Cleveland and Cleveland Veterans Administration Hospital (1981-1984)
M.D., Columbia University College of Physicians & Surgeons (1977-1981)
A.B., Columbia College, Columbia University (1973-1977)
For more than 2 decades, our laboratory studied the structure and function of the retroviral integrase enzyme that is responsible for catalyzing the permanent integration of a copy of the viral genome into the DNA of an infected cell. We have worked with the integrases of human immunodeficiency virus (HIV), avian sarcoma viruses, and visna virus with the goal of understanding the mechanism of integration so as to develop new ways to prevent or treat the acquired immunodeficiency syndrome (AIDS), but this work is also relevant to certain other human diseases, some animal models of cancer, and gene therapy.
In particular, several years ago I participated in the first purification of an enzymatically active retroviral integrase from a bacterial expression system and developed an assay that is used throughout the world to study this enzyme. After establishing my own laboratory, we created the first set of functional chimeric lentiviral integrases by making novel proteins partly from HIV and partly from a sheep virus; these studies identified the parts of integrase that interact with viral DNA and with human DNA, while also identifying the parts of viral DNA that interact with integrase. We then characterized the largest set (to that point) of HIV integrases derived from infected patients; these studies identified an amino acid in the middle of the protein that likely contacts human DNA during integration. Subsequently, we made several mutations at the position identified by the human samples to yield novel integrases that were improved at acting on viral DNA but impaired at acting on cellular DNA, the first mutants to separate the two biologically relevant actions of integrase in this way. More recent work tried to exploit these properties to define the cellular-DNA and viral-DNA binding sites on the integrase protein. In another project, we explored the potential of stimulating the ability of integrase to nick DNA nonspecifically for a novel antiviral strategy of using integrase to damage viral DNA. Our focus on integrase has contributed to the current model of retroviral integration and will enhance efforts to target specific actions or domains of integrase for clinical therapy. The recent introduction of integrase inhibitors into clinical practice for treating HIV infection has been particularly gratifying.
With the evolution of my career, I have now shifted focus to the appropriate usage of antimicrobial drugs in the healthcare setting, and in 2011 we established a successful Antimicrobial Stewardship Program at Penn State Hershey Medical Center.
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