: Kaposi's sarcoma is a highly vascular skin lesion consisting of clonal and polyc!onal expansions of endothelial cell derived spindle cells that carry multiple copy episomal genomes of the newest human herpesvirus to be discovered, referred to as KSHV or HHV8. Seropositivity for KSHV infection in the USA, Europe and Asia is low, but the risk factor for KS in male homosexual AIDS patients in increased 20,000 fold, with up to 20 percent developing lesions and 50 to 85 percent becoming infected. KS is now also the most commonly encountered tumor in Sub-Saharan Africa, where HIV has spread into a population that was nearly ubiquitously infected with KSHV, as well as in renal transplant patients in other populations with relatively high endemic KSHV infection rates. The DNA genome of KSHV differs from that of EBV by lacking all of the latent state EBNA genes, but instead encodes a set of captured cellular genes, including cytokines, chemokines, cyclin and chemokine receptor genes, that have novel anti-apoptotic and angiogenic properties. In this competitive renewal, we propose to continue our studies of the early stages of KSHV lytic cycle infection in both PEL lymphocytes and primary dermal microvascular endothelial cells. These experiments will focus on the viral and cellular proteins involved in the switch from latent to lytic infection, the earliest stages of transcriptional regulation, and the initiation of lytic DNA replication, as well as the regulatory interactions between transcription control and DNA replication. The three Specific Aims encompass; firstly, examination of the patterns of viral and altered cellular gene expression in lytic infection in vascular endothelial cells; secondly, studies of the cis-acting domains and trans-acting factors that participate in the switch from latent to lytic cycle infection, with emphasis on the role of the RTA(ORF50) transactivator and differential promoter regulation; thirdly, analysis of the mechanism and control of KSHV DNA replication, especially related to identifying and studying ori-Lyt and the predicted origin binding protein, as well as the role of ORF-K8 C/EBP and cell cycle controls.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA073585-07
Application #
6622599
Study Section
Special Emphasis Panel (ZRG1-AARR-4 (01))
Program Officer
Read-Connole, Elizabeth Lee
Project Start
1996-09-30
Project End
2006-11-30
Budget Start
2002-12-01
Budget End
2003-11-30
Support Year
7
Fiscal Year
2003
Total Cost
$397,493
Indirect Cost
Name
Johns Hopkins University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Ehrlich, Elana S; Chmura, Jennifer C; Smith, John C et al. (2014) KSHV RTA abolishes NF?B responsive gene expression during lytic reactivation by targeting vFLIP for degradation via the proteasome. PLoS One 9:e91359
Yu, Yanxing; Hayward, Gary S (2010) The ubiquitin E3 ligase RAUL negatively regulates type i interferon through ubiquitination of the transcription factors IRF7 and IRF3. Immunity 33:863-77
Davison, Andrew J; Eberle, Richard; Ehlers, Bernhard et al. (2009) The order Herpesvirales. Arch Virol 154:171-7
Hayward, G S; Zong, J C (2007) Modern evolutionary history of the human KSHV genome. Curr Top Microbiol Immunol 312:1-42
Zong, Jian-Chao; Arav-Boger, Ravit; Alcendor, Donald J et al. (2007) Reflections on the interpretation of heterogeneity and strain differences based on very limited PCR sequence data from Kaposi's sarcoma-associated herpesvirus genomes. J Clin Virol 40:1-8
Zong, Jian-Chao; Kajumbula, Henry; Boto, William et al. (2007) Evaluation of global clustering patterns and strain variation over an extended ORF26 gene locus from Kaposi's sarcoma herpesvirus. J Clin Virol 40:19-25
Huang, Jian; Liao, Gangling; Chen, Honglin et al. (2006) Contribution of C/EBP proteins to Epstein-Barr virus lytic gene expression and replication in epithelial cells. J Virol 80:1098-109
Yu, Yanxing; Wang, Shizhen Emily; Hayward, Gary S (2005) The KSHV immediate-early transcription factor RTA encodes ubiquitin E3 ligase activity that targets IRF7 for proteosome-mediated degradation. Immunity 22:59-70
Wang, Shizhen Emily; Wu, Frederick Y; Chen, Honglin et al. (2004) Early activation of the Kaposi's sarcoma-associated herpesvirus RTA, RAP, and MTA promoters by the tetradecanoyl phorbol acetate-induced AP1 pathway. J Virol 78:4248-67
Wu, Frederick Y; Wang, Shizhen Emily; Chen, Honglin et al. (2004) CCAAT/enhancer binding protein alpha binds to the Epstein-Barr virus (EBV) ZTA protein through oligomeric interactions and contributes to cooperative transcriptional activation of the ZTA promoter through direct binding to the ZII and ZIIIB motifs during J Virol 78:4847-65

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