Biomedical Sciences Graduate Program(s)
Biomedical Sciences Graduate Programs
Pathogenesis of Kaposi’s Sarcoma-Associated Herpesvirus
--using approaches from virology, infectious diseases, immunology, and both cell and molecular biology--
Kaposi's sarcoma (KS), the 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. 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 the virus’s ability to evade host cell defenses as well as to activate and potentially exploit host signal transduction pathways.
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), immuno-EM and cryo-EM.
3. Animal models of viral infection: Development of a transgenic and xenograft (humanized) mouse models of KSHV infection that will allow us to monitor the cellular immune response to viral proteins, taking advantage of a transgenic mice expressing human HLA molecules.
4. Viral tropism in patients: 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.
Adang, L.A, Tomescu, C., Law, W.K., and Kedes, D.H. Intracellular KSHV load determines early loss of immune synapse components Journal of Virology 2007, 81:5079-5090.
Adang, L.A., Parsons, C.H. and Kedes, D.H. Asynchronous progression through the lytic cascade and variations in intracellular viral loads revealed by high-throughput single cell analysis of KSHV infection Journal of Virology 2006, 80:10073-10082.
Parsons, C.H., Adang, L.A., Overdevest, J., O’Connor, C., Camerini, D., and Kedes, D.H. KSHV targets multiple leukocyte lineages during long-term productive infection in NOD/SCID mice. J. Clin. Invest. 2006 116:1963-1973.
O’Connor, C. and Kedes, D.H. Mass Spectrometric Analyses of Purified Rhesus Monkey Rhadinovirus Reveal 33 Virion-Associated Proteins Journal of Virology 2006, 80(3):1574-1583.
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