Kaposi's Sarcoma (KS) was the most common tumor in Aids patients in this country before the wide spread use of highly active antiretroviral therapy. KS is currently the most commonly reported tumor in regions of Africa. Kaposi's Sarcoma-associated herpesvirus (KSHV, formally known as human herpesvirus 8, HHV-8) is an essential etiologic agent for KS. In KS, KSHV is found in the spindle cell, a cell of endothelial origin that is the tumor cell of KS. KSHV is also associated with primary effusion lymphoma (PEL), a B-cell lymphoproliferative disorder. PEL cell lines have been created and are used for many studies of KSHV. However, KS is an endothelial cell based neoplasm and thus it is important to study KSHV in endothelial cells as well. Herpesviruses are all characterized by having latent infection, where the virus is maintained for the life of the host but does not produce infectious particles, and lytic infection, where the virus replicates and lyses the host cell. Interestingly, KS apparently requires both lytic and latent phase infection for formation and maintenance. Since the lytically infected cell is dying, there must be paracrine factors produced that act on latently infected cells. We propose to characterize the function of lytic gene expression in maintenance of KS by studying the role of lytic genes in latently infected endothelial cells. We have created a tractable system for studying KSHV in endothelial cells and we will study KSHV gene expression and function in our endothelial cell system. We will create and purify recombinant KSHV isolates deleted in prominent lytic genes involved in signal transduction. Subsequent analysis will characterize the role of these genes in both lytic and latent infection. We will analyze growth and signaling capabilities during lytic infection and we will analyze how these lytic genes alter host transcription in latently infected cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA097934-01A1
Application #
6655992
Study Section
AIDS and Related Research 8 (AARR)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2003-04-01
Project End
2008-03-31
Budget Start
2003-04-01
Budget End
2004-03-31
Support Year
1
Fiscal Year
2003
Total Cost
$257,816
Indirect Cost
Name
University of Washington
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
DiMaio, Terri A; Wentz, Breanna L; Lagunoff, Michael (2016) Isolation and characterization of circulating lymphatic endothelial colony forming cells. Exp Cell Res 340:159-69
Sanchez, Erica L; Lagunoff, Michael (2015) Viral activation of cellular metabolism. Virology 479-480:609-18
Fontaine, Krystal A; Sanchez, Erica L; Camarda, Roman et al. (2015) Dengue virus induces and requires glycolysis for optimal replication. J Virol 89:2358-66
Fontaine, Krystal A; Camarda, Roman; Lagunoff, Michael (2014) Vaccinia virus requires glutamine but not glucose for efficient replication. J Virol 88:4366-74
DiMaio, Terri A; Gutierrez, Kimberley D; Lagunoff, Michael (2014) Kaposi's sarcoma-associated herpesvirus downregulates transforming growth factor ?2 to promote enhanced stability of capillary-like tube formation. J Virol 88:14301-9
Gutierrez, Kimberley D; Morris, Valerie A; Wu, David et al. (2013) Ets-1 is required for the activation of VEGFR3 during latent Kaposi's sarcoma-associated herpesvirus infection of endothelial cells. J Virol 87:6758-68
Delgado, Tracie; Sanchez, Erica L; Camarda, Roman et al. (2012) Global metabolic profiling of infection by an oncogenic virus: KSHV induces and requires lipogenesis for survival of latent infection. PLoS Pathog 8:e1002866
Dimaio, Terri A; Lagunoff, Michael (2012) KSHV Induction of Angiogenic and Lymphangiogenic Phenotypes. Front Microbiol 3:102
Morris, Valerie A; Punjabi, Almira S; Wells, Robert C et al. (2012) The KSHV viral IL-6 homolog is sufficient to induce blood to lymphatic endothelial cell differentiation. Virology 428:112-20
DiMaio, Terri A; Gutierrez, Kimberley D; Lagunoff, Michael (2011) Latent KSHV infection of endothelial cells induces integrin beta3 to activate angiogenic phenotypes. PLoS Pathog 7:e1002424

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