Dean H. Kedes

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Primary Appointment

Professor, Microbiology, Immunology, and Cancer Biology

Education

  • BS, Biology, Stanford University
  • MD, Yale School of Medicine
  • PhD, Molecular Biophysics and Biochemistry, Yale University

Research Disciplines

Biophysics, Biotechnology, Cancer Biology, Immunology, Infectious Diseases/Biodefense

Research Interests

Human Herpes virus associated with malignancy, including Kaposi's Sarcoma

Research Description

Pathogenesis of Kaposi's Sarcoma-Associated Herpesvirus
Kaposi's sarcoma (KS) remains one of the two most common AIDS-associated malignancies and is caused by the human herpesvirus, KSHV, first discovered in 1994. Nevertheless, many details of KSHV infection and pathogenesis remain unclear. A rare type of B cell lymphoma (PEL) also arising from KSHV infection, has allowed the development of cell lines that produce KSHV in culture. These lines, along with a manipulable bacterial artificial chromosome of the approximately 165kbp viral genome, have allowed the study of viral structure, assembly, gene expression and pathogenesis. Examining both KSHV and its close non-human primate pathogen, rhesus monkey rhadinovirus (RRV), we have focused on the following four major areas:
1. Viral gene culprits: Isolation and characterization of viral genes and their protein products involved in KSHV pathogenesis. In particular we are interested in the mechanisms underlying a) the activation of cellular signaling during viral entry and b) the pathway of viral egress, including the affects of viral gene products on the cytoskeleton.
2. Viral structure and proteomics: Determination of the protein composition, spatial arrangement and assembly of viral and subviral particles. Our approaches include the coupling of classical molecular biology and virology with biochemistry, electron microscopy (EM), and, through collaborations with colleagues that include Pew Scholar, Z. Hong Zhu (UCLA), immuno-EM and cryo-EM.
3. Viral tropism in patients: Identification of the cell types initially infected during primary transmission of KSHV in humans.
4. Investigations into the structural connection between viral and human genomes during latent (chronic) infection, in a collaborative effort with the laboratory of Mitchell Smith and using sub-nanometer microscopy.

Personal Statement

Pathogenesis of Kaposiâs Sarcoma-Associated Herpesvirus

Kaposi's sarcoma (KS), one of the two most common AIDS-associated malignancy, is caused by the human herpesvirus, KSHV. Nevertheless, the details of KSHV infection and pathogenesis remain unclear. A rare type of B cell lymphoma (PEL) also arising from KSHV infection, has allowed the development of cell lines that produce KSHV in culture. These lines have allowed the study of viral structure, assembly, gene expression and pathogenesis. Our investigations involve four major areas:


1. Isolation and characterization of viral genes and their protein products involved in KSHV pathogenesis. In particular we are interested in the mechanisms underlying the virusâs ability to evade host cell defenses as well as to activate and potentially exploit host signal transduction pathways.


2. Determination of the protein composition, spatial arrangement and assembly of viral and subviral particles. Our approaches include the coupling of classical molecular biology and virology with biochemistry, electron microscopy (EM), immuno-EM and cryo-EM.


3. Development of a transgenic mouse model of KSHV infection that will allow us to monitor the cellular immune response to viral proteins (antigens), taking advantage of a transgenic mice expressing human HLA molecules.


4. Identification of the cell types initially infected during primary transmission of KSHV in humans, including understanding better the intracellular milieu favoring latent versus lytic stages of the viral life cycle.

Training

  • Biodefense & Infectious Diseases Short-Term Training to Increase Diversity in Biomedical Sciences
  • Training in Cell and Molecular Biology

Selected Publications

2018

Grant, M. J., Loftus, M. S., Stoja, A. P., Kedes, D. H., & Smith, M. (2018). Superresolution microscopy reveals structural mechanisms driving the nanoarchitecture of a viral chromatin tether. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 115(19), 4992-4997. doi:10.1073/pnas.1721638115

2017

Loftus, M. S., Verville, N., & Kedes, D. H. (2017). A Conserved Leucine Zipper Motif in Gammaherpesvirus ORF52 Is Critical for Distinct Microtubule Rearrangements. JOURNAL OF VIROLOGY, 91(17). doi:10.1128/JVI.00304-17

2014

Ellison, T. J., & Kedes, D. H. (2014). Variable Episomal Silencing of a Recombinant Herpesvirus Renders Its Encoded GFP an Unreliable Marker of Infection in Primary Cells. PLOS ONE, 9(11). doi:10.1371/journal.pone.0111502

Woodson, E. N., Anderson, M. S., Loftus, M. S., & Kedes, D. H. (2014). Progressive Accumulation of Activated ERK2 within Highly Stable ORF45-Containing Nuclear Complexes Promotes Lytic Gammaherpesvirus Infection. PLOS PATHOGENS, 10(4). doi:10.1371/journal.ppat.1004066

Zhou, Z. H., Hui, W. H., Shah, S., Jih, J., O'Connor, C. M., Sherman, M. B., . . . Schein, S. (2014). Four Levels of Hierarchical Organization, Including Noncovalent Chainmail, Brace the Mature Tumor Herpesvirus Capsid against Pressurization. STRUCTURE, 22(10), 1385-1398. doi:10.1016/j.str.2014.05.019

Anderson, M. S., Loftus, M. S., & Kedes, D. H. (2014). Maturation and Vesicle-Mediated Egress of Primate Gammaherpesvirus Rhesus Monkey Rhadinovirus Require Inner Tegument Protein ORF52. JOURNAL OF VIROLOGY, 88(16), 9111-9128. doi:10.1128/JVI.01502-14

2012

Borah, S., Nichols, L. A., Hassman, L. M., Kedes, D. H., & Steitz, J. A. (2012). Tracking expression and subcellular localization of RNA and protein species using high-throughput single cell imaging flow cytometry. RNA, 18(8), 1573-1579. doi:10.1261/rna.033126.112

Woodson, E. N., & Kedes, D. H. (2012). Distinct Roles for Extracellular Signal-Regulated Kinase 1 (ERK1) and ERK2 in the Structure and Production of a Primate Gammaherpesvirus. JOURNAL OF VIROLOGY, 86(18), 9721-9736. doi:10.1128/JVI.00695-12

2011

Hassman, L. M., Ellison, T. J., & Kedes, D. H. (2011). KSHV infects a subset of human tonsillar B cells, driving proliferation and plasmablast differentiation. JOURNAL OF CLINICAL INVESTIGATION, 121(2), 752-768. doi:10.1172/JCI44185

Nichols, L. A., Adang, L. A., & Kedes, D. H. (2011). Rapamycin Blocks Production of KSHV/HHV8: Insights into the Anti-Tumor Activity of an Immunosuppressant Drug. PLOS ONE, 6(1). doi:10.1371/journal.pone.0014535