There is a fundamental gap in our understanding of how animal virus interactions with cell surface receptors facilitate a productive infection. Bindin of viruses, such as herpesviruses, to the cell surface can occur at 40C in an energy independent manner. In contrast, entry into cells and subsequent transfer of capsids to the vicinity of the nucleus are an active, energy dependent phenomenon, and thus must require host-cell signaling pathways. Our central hypothesis is that KSHV has evolved to utilize its interactions with receptors to manipulate the host's pre-existing signal cascades to mediate entry and infection of target cells. Our ongoing studies support this hypothesis. We have shown that during infection of endothelial (HMVEC-d) cells, the initial attachment of KSHV occurs via heparan sulfate (HS) followed by a temporal interaction with integrins (?3?1,??V??3, and ?V??5) and xCT molecules. KSHV binding resulted in the activation of FAK, Src, PI3-K, Rho-GTPases, Dia-2, Ezrin, PKC-?, ERK1/2 and NF-?B signal molecules. These molecules play roles in KSHV entry (FAK, Src, PI3-K, Rho-GTPases), acetylation of microtubules (MT) (RhoA-GTPase) that facilitates the transport of KSHV capsid toward the nucleus via dynein motors, and viral gene expression (ERK1/2 and NF-?B). Although lipid raft (LR) disruption resulted in increased Src activation and virus entry, we observed the inhibition of viral gene expression, PI3K, RhoA, Dia-2 and NF?B activation, MT acetylation and nuclear delivery of viral DNA which suggested that LRs play roles in entry in cells and modulates selected signal molecules. We have also demonstrated that c-Cbl play a role in KSHV macropinocytosis. To further test our hypothesis, we have formulated three major interlinked, focused specific aims which will decipher the mechanisms by which c-Cbl facilitate KSHV entry, the role of major adaptor molecules in KSHV infection and decipher how c-Cbl dictates the fate of macropinosomes containing KSHV. These studies are significant since such comprehensive understanding of early events of KSHV infection will provide novel targets to block the initiation of target cell infection by KSHV and te associated diseases.

Public Health Relevance

Kaposi's sarcoma associated herpesvirus (KSHV) is etiologically associated with Kaposi's sarcoma and primary effusion lymphoma. The proposed studies will investigate early events of in vitro infection by KSHV. These studies are significant since such comprehensive understanding of early events of KSHV infection will provide novel targets to block the initiation of target cell infection by KSHV and the associated diseases.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
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Read-Connole, Elizabeth Lee
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Rosalind Franklin University
Schools of Medicine
North Chicago
United States
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Kumar, Binod; Roy, Arunava; Veettil, Mohanan Valiya et al. (2018) Insight into the Roles of E3 Ubiquitin Ligase c-Cbl, ESCRT Machinery, and Host Cell Signaling in Kaposi's Sarcoma-Associated Herpesvirus Entry and Trafficking. J Virol 92:
Veettil, Mohanan Valiya; Kumar, Binod; Ansari, Mairaj Ahmed et al. (2016) ESCRT-0 Component Hrs Promotes Macropinocytosis of Kaposi's Sarcoma-Associated Herpesvirus in Human Dermal Microvascular Endothelial Cells. J Virol 90:3860-3872
Gjyshi, Olsi; Roy, Arunava; Dutta, Sujoy et al. (2015) Activated Nrf2 Interacts with Kaposi's Sarcoma-Associated Herpesvirus Latency Protein LANA-1 and Host Protein KAP1 To Mediate Global Lytic Gene Repression. J Virol 89:7874-92
Gjyshi, Olsi; Flaherty, Stephanie; Veettil, Mohanan Valiya et al. (2015) Kaposi's sarcoma-associated herpesvirus induces Nrf2 activation in latently infected endothelial cells through SQSTM1 phosphorylation and interaction with polyubiquitinated Keap1. J Virol 89:2268-86
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
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
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
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

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