- Professor, Department of Pediatrics, Committee on Microbiology
M.D., Ph.D., University of Washington
The University of Chicago
C638, (MC 6054)
5841 South Maryland Avenue
Chicago, Illinois 60637
Phone: (773) 702-6176
Human Papillomavirus Transcription Control, DNA Replication, Innate Immune Responses and Antiviral Therapy
Human papillomaviruses (HPVs) cause anogenital dysplasias, laryngeal papillomatosis, and common warts. Replication of papillomaviruses requires a differentiating epithelium. Within HPV-infected epithelia, transcription of viral proteins and replication of viral DNA are linked with the process of keratinocyte differentiation. Our research focuses on the biochemical mechanisms that coordinate transcription and replication in human papillomaviruses, and link these processes with keratinocyte differentiation.
Papillomavirus transcription is controlled by the virus-encoded E2 protein. E2 interacts with a variety of host cell proteins, including components of the host cell TFIID complex. One project in the laboratory seeks to discern what components of the TFIID complex interact with E2, and how these interactions affect transcription of both viral and host cell genes.
In a second project, the interactions of the papillomavirus E1 protein (a DNA helicase/ATPase) with host cell proteins are being investigated to determine how viral DNA replication is controlled.
A third line of investigation is directed at the study of chemically modified short interfering RNAs (siRNAs). siRNAs in which the bridging phosphodiester linkages have been replaced with a boranophosphate links show high gene silencing activity, and function as single strands. The goals of this project are to make further improvements in siRNA activity and stability, to discern the biochemical bases for the potent gene silencing activity of boranophosphate siRNAs, and to use our understanding of modified siRNAs to develop highly active, highly stable siRNAs that function as antiviral microbicides.
A newly developing area of research in the laboratory is characterizing the effects of HPV E6 on the signalling pathways that control innate immunity.
Alexander KA and Phelps WC. (2000). Recent Advances in Diagnosis and Treatment of Human Papillomaviruses. Exp. Opin. Invest. Drugs 9(8): 1753-1765
Hall AHS and Alexander KA. (2003). RNA Interference of HPV18 E6 and E7 Induces Senescence in HeLa Cells. J. Virology 77(10): 6066-6069
Hall AHH, Wan J, Shaughnessy EE, Ramsay Shaw B and Alexander KA. (2004). RNA interference using boranophosphate siRNAs: structure-activity relationships. Nucleic Acids Research 32(20): 5991-6000
Alexander KA. (2005). Diagnosis and Treatment of Human Papillomavirus Infections. Pediatr. Inf. Dis. J. 24(11): 1007-1008
Hall AHH, Wan J, Spesock A, Ramsay Shaw B and Alexander KA. (2006). High potency silencing by single-stranded boranophosphate siRNA. Nucleic Acids Research 34(9): 2773-2781.
McCall SJ, Alexander KA, Oakley AE, Ackley J, Nasser R, Pielak G, Anderson PAW and Malouf N. (2006). Development and cardiac contractility: Cardiac troponin T isoforms and cytosolic calcium in rabbit. Pediatric Research 60: 276-271.