Kaposi's sarcoma-associated herpesvirus (KSHV) is etiologically associated in the pathogenesis of Kaposi's sarcoma (KS), an AIDS-defining vascular tumor. Our long term objectives are to examine KSHV infection of endothelial cells and role in KS pathogenesis. To determine the role of lytic replication in KS pathogenesis, we focused on KSHV interactions with cell surface molecules and examined the interactions of KSHV-gB with integrin molecules. We have demonstrated that KSHV interacts with integrins of adherent target cells which overlaps with the induction of pre-existing integrin associated host cell signal pathways, such as FAK, Src, PI3-K, Rho-GTPases, Dia-2, PKC, ERK1/2 and NF-kB pathways that are critical for virus entry, nuclear delivery and initiation of viral gene expression. These novel paradigms in the field of virus-receptor interactions suggest that KSHV interaction with host cell receptors has evolved not to be a mere conduit for viral DNA entry, but has evolved to manipulate the host cell signaling pathways to create an appropriate intracellular environment that is conducive to the establishment of a successful infection. We hypothesize that KSHV interacts with a family of functionally related endothelial cell surface molecules, such as ?3?1, ?V?3/?V?5 and CD98-xCT, in a sequentially co- coordinated manner to mediate its binding, entry and infection. To test the hypothesis, we have formulated the following four major specific aims. 1. To decipher the temporal sequence of KSHV interactions with endothelial cell surface ?3?1, ?V?3 and ?V?5 integrins, and to determine the role of KSHV-gB disintegrin, gpK8.1A-NGR and gH-SGD motifs in integrin interactions. 2. To decipher KSHV interactions with endothelial CD98/xCT molecules, their associations with integrins, to identify the KSHV envelope glycoproteins involved in the interactions, and to define the interactions of recombinant gpK8.1A deleted KSHV with integrins, CD98 and xCT molecules. 3. To decipher the role of CD98-xCT in KSHV infection of endothelial cells and to define the stage at which CD98-xCT play roles. 4. To decipher the role of integrins, CD98, xCT, ROS and Nrf2 molecules in KSHV induced endothelial cell signal pathways during the early stages of infection. These studies are significant as deciphering the host cell receptors involved in the early stages of KSHV interactions with endothelial cells will lead to a better understanding of KSHV tropism and pathogenesis and to the development of strategies to control KSHV infection associated KS and other diseases. Kaposi's sarcoma-associated herpesvirus (KSHV) or HHV-8 is etiologically associated in the pathogenesis of Kaposi's sarcoma (KS), an AIDS-defining vascular tumor. Our studies suggest that KSHV interacts with a family of functionally related endothelial cell surface molecules not only to mediate the entry of viral DNA into the target cells but also to manipulate the host cell signaling pathways to create an appropriate intracellular environment that is conducive to the establishment of a successful infection. Deciphering the interactions between KSHV and host cell receptors involved in the early stages of infection of endothelial cells will lead to a better understanding of tropism and pathogenesis of KSHV and to the development of strategies to control KSHV infection and associated diseases.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA075911-16
Application #
8278684
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
1998-04-01
Project End
2013-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
16
Fiscal Year
2012
Total Cost
$300,866
Indirect Cost
$105,498
Name
Rosalind Franklin University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
069501252
City
North Chicago
State
IL
Country
United States
Zip Code
60064
Bandyopadhyay, Chirosree; Veettil, Mohanan Valiya; Dutta, Sujoy et al. (2014) p130Cas scaffolds the signalosome to direct adaptor-effector cross talk during Kaposi's sarcoma-associated herpesvirus trafficking in human microvascular dermal endothelial cells. J Virol 88:13858-78
Veettil, Mohanan Valiya; Bandyopadhyay, Chirosree; Dutta, Dipanjan et al. (2014) Interaction of KSHV with host cell surface receptors and cell entry. Viruses 6:4024-46
Bandyopadhyay, Chirosree; Valiya-Veettil, Mohanan; Dutta, Dipanjan et al. (2014) CIB1 synergizes with EphrinA2 to regulate Kaposi's sarcoma-associated herpesvirus macropinocytic entry in human microvascular dermal endothelial cells. PLoS Pathog 10:e1003941
Gjyshi, Olsi; Bottero, Virginie; Veettil, Mohanan Valliya et al. (2014) Kaposi's sarcoma-associated herpesvirus induces Nrf2 during de novo infection of endothelial cells to create a microenvironment conducive to infection. PLoS Pathog 10:e1004460
Valiya Veettil, Mohanan; Dutta, Dipanjan; Bottero, Virginie et al. (2014) Glutamate secretion and metabotropic glutamate receptor 1 expression during Kaposi's sarcoma-associated herpesvirus infection promotes cell proliferation. PLoS Pathog 10:e1004389
Singh, Vivek Vikram; Dutta, Dipanjan; Ansari, Mairaj Ahmed et al. (2014) Kaposi's sarcoma-associated herpesvirus induces the ATM and H2AX DNA damage response early during de novo infection of primary endothelial cells, which play roles in latency establishment. J Virol 88:2821-34
Dutta, Dipanjan; Chakraborty, Sayan; Bandyopadhyay, Chirosree et al. (2013) EphrinA2 regulates clathrin mediated KSHV endocytosis in fibroblast cells by coordinating integrin-associated signaling and c-Cbl directed polyubiquitination. PLoS Pathog 9:e1003510
Johnson, Karen E; Chikoti, Leela; Chandran, Bala (2013) Herpes simplex virus 1 infection induces activation and subsequent inhibition of the IFI16 and NLRP3 inflammasomes. J Virol 87:5005-18
Singh, Vivek Vikram; Kerur, Nagaraj; Bottero, Virginie et al. (2013) Kaposi's sarcoma-associated herpesvirus latency in endothelial and B cells activates gamma interferon-inducible protein 16-mediated inflammasomes. J Virol 87:4417-31
Bottero, Virginie; Chakraborty, Sayan; Chandran, Bala (2013) Reactive oxygen species are induced by Kaposi's sarcoma-associated herpesvirus early during primary infection of endothelial cells to promote virus entry. J Virol 87:1733-49

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