HOST FACTORS CONTROLLING VIRUS INFECTION: IMPLICATIONS FOR ANTIVIRALS AND VIROTHERAPY

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Shah, N. (2013). HOST FACTORS CONTROLLING VIRUS INFECTION: IMPLICATIONS FOR ANTIVIRALS AND VIROTHERAPY. Unc Charlotte Electronic Theses And Dissertations.
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Abstract

Viruses are obligate intracellular parasites rely heavily on host components and pathways for their replication. Studying different cellular factors affecting viral infection can enable us to identify novel drug targets, improve current antiviral treatments and improve efficacy of virus based therapies. This dissertation examines two prototypic members of an order Mononegavirales, vesicular stomatitis virus (VSV) and Sendai virus (SeV) and is focused on: 1) resistance of some hosts to a broad spectrum antiviral drug ribavirin and 2) resistance of some pancreatic cancers to oncolytic virotherapy. Here, for the first time we examined whether certain cell types are naturally resistant to ribavirin even without prior drug exposure. Our results show striking differences between cell types in their response to ribavirin. Our data also suggest that this resistance was due to cellular factors rather than viral determinants and ribavirin may inhibit the same virus via different mechanisms in different cells depending on the ribavirin metabolism. Additionally, resistance of oncolytic VSV therapy in specific human pancreatic ductal adenocarcinoma (PDA) cells was investigated and this resistance was attributed to constitutive expression of the IFN-stimulated antiviral genes MxA and OAS. Decreasing the levels of MxA and OAS by inhibition of JAK/STAT signaling, improved VSV infection and oncolysis. Overall, our study demonstrated heterogeneity in the type I IFN signaling status of PDA cells and suggests MxA and OAS as potential biomarkers for PDA resistance to VSV and other oncolytic viruses (OVs) sensitive to type I IFN responses.

Details
Author

Shah, Nirav

Title

HOST FACTORS CONTROLLING VIRUS INFECTION: IMPLICATIONS FOR ANTIVIRALS AND VIROTHERAPY

Physical Description

1 online resource (151 pages) : PDF

Date

2013

Degree Granting Institution

University of North Carolina at Charlotte

Abstract

Viruses are obligate intracellular parasites rely heavily on host components and pathways for their replication. Studying different cellular factors affecting viral infection can enable us to identify novel drug targets, improve current antiviral treatments and improve efficacy of virus based therapies. This dissertation examines two prototypic members of an order Mononegavirales, vesicular stomatitis virus (VSV) and Sendai virus (SeV) and is focused on: 1) resistance of some hosts to a broad spectrum antiviral drug ribavirin and 2) resistance of some pancreatic cancers to oncolytic virotherapy. Here, for the first time we examined whether certain cell types are naturally resistant to ribavirin even without prior drug exposure. Our results show striking differences between cell types in their response to ribavirin. Our data also suggest that this resistance was due to cellular factors rather than viral determinants and ribavirin may inhibit the same virus via different mechanisms in different cells depending on the ribavirin metabolism. Additionally, resistance of oncolytic VSV therapy in specific human pancreatic ductal adenocarcinoma (PDA) cells was investigated and this resistance was attributed to constitutive expression of the IFN-stimulated antiviral genes MxA and OAS. Decreasing the levels of MxA and OAS by inhibition of JAK/STAT signaling, improved VSV infection and oncolysis. Overall, our study demonstrated heterogeneity in the type I IFN signaling status of PDA cells and suggests MxA and OAS as potential biomarkers for PDA resistance to VSV and other oncolytic viruses (OVs) sensitive to type I IFN responses.

Genre

doctoral dissertations

Subjects--Topics

Virology
Oncology

Degree

Ph.D.

Keywords

Antiviral
Host Factors
Oncolytic Viruses
Pancreatic Cancer
Ribavirin
VSV

Subject Area

Biology

Advisor(s)

Grdzelishvili, Valery

Committee Members

Mukherjee, Pinku
Nelson, Dan
Schrum, Laura
Turner, Mike

Degree Note

Thesis (Ph.D.)--University of North Carolina at Charlotte, 2013.

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Rights Holder Information

Copyright is held by the author unless otherwise indicated.

Identifier

Shah_uncc_0694D_10424

Permalink

http://hdl.handle.net/20.500.13093/etd:487