A decade of both epidemiologic and biologic research has firmly established Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) as the infectious cause of the tumor that shares its name. Infection with this gammaherpesvirus can also lead to two other human diseases, multicentric Castlemen's disease, a lymphoproliferative disorder, and primary effusion lymphoma, a B cell tumor most often afflicting persons with acquired immune deficiency syndrome (AIDS). Although initial KSHV exposure is generally asymptomatic and likely results in the latent infection of a limited number of cells in the host, immunosuppression can lead to unchecked viral spread, expansion of latently infected cells and eventual tumor formation. This pathogenic progression as well as person-to-person spread depends on lytic reactivation and replication of virus followed by recruitment, infection and hyperplastic expansion of a critical mass of new target cells. The most remarkable structures to appear following the initiation of lytic replication are the icosahedral capsids that fill the nucleus and, when fully mature, harbor the linear viral genome. Our NIH-sponsored work on KSHV during the initialfunding period was the first to explore simultaneously the protein composition, stoichiometry andthree-dimensional structure of capsids from a gammaherpesvirus. We propose in this application to extend these studies toward a comprehensive understanding of the composition and structure of the virions, examining both KSHV and its useful primate homolog, Rhesus monkey rhadinovirus (RRV). Since virions must contain the proteins essential for host range determination and initiation of infection, it is critical to comprehensively identify their protein composition. Moreover, knowledge of this composition is a prerequisite for functional investigations. Wewill integrate molecular and imaging techniques to identify the virion-associated proteins and the genes encoding them while characterizing the finer details of the viral architecture. The results of our proposed studies on viral structure, molecular composition and assembly may help identify new targets for therapeutic intervention in the future.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
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Ogunbiyi, Peter
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University of Virginia
Internal Medicine/Medicine
Schools of Medicine
United States
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Loftus, Matthew S; Verville, Nancy; Kedes, Dean H (2017) A Conserved Leucine Zipper Motif in Gammaherpesvirus ORF52 Is Critical for Distinct Microtubule Rearrangements. J Virol 91:
Anderson, Melissa S; Loftus, Matthew S; Kedes, Dean H (2014) Maturation and vesicle-mediated egress of primate gammaherpesvirus rhesus monkey rhadinovirus require inner tegument protein ORF52. J Virol 88:9111-28
Woodson, Evonne N; Anderson, Melissa S; Loftus, Matthew S et al. (2014) Progressive accumulation of activated ERK2 within highly stable ORF45-containing nuclear complexes promotes lytic gammaherpesvirus infection. PLoS Pathog 10:e1004066
Zhou, Z Hong; Hui, Wong Hoi; Shah, Sanket et al. (2014) Four levels of hierarchical organization, including noncovalent chainmail, brace the mature tumor herpesvirus capsid against pressurization. Structure 22:1385-98
Woodson, Evonne N; Kedes, Dean H (2012) Distinct roles for extracellular signal-regulated kinase 1 (ERK1) and ERK2 in the structure and production of a primate gammaherpesvirus. J Virol 86:9721-36
Hassman, Lynn M; Ellison, Thomas J; Kedes, Dean H (2011) KSHV infects a subset of human tonsillar B cells, driving proliferation and plasmablast differentiation. J Clin Invest 121:752-68
Nichols, Lisa A; Adang, Laura A; Kedes, Dean H (2011) Rapamycin blocks production of KSHV/HHV8: insights into the anti-tumor activity of an immunosuppressant drug. PLoS One 6:e14535
Deng, Binbin; O'Connor, Christine M; Kedes, Dean H et al. (2008) Cryo-electron tomography of Kaposi's sarcoma-associated herpesvirus capsids reveals dynamic scaffolding structures essential to capsid assembly and maturation. J Struct Biol 161:419-27
Adang, Laura A; Tomescu, Costin; Law, Wai K et al. (2007) Intracellular Kaposi's sarcoma-associated herpesvirus load determines early loss of immune synapse components. J Virol 81:5079-90
Deng, Binbin; O'Connor, Christine M; Kedes, Dean H et al. (2007) Direct visualization of the putative portal in the Kaposi's sarcoma-associated herpesvirus capsid by cryoelectron tomography. J Virol 81:3640-4

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