Dissertation
MECHANISM AND SYNERGISTIC POTENTIAL OF BORTEZOMIB AS AN ANTIHERPESVIRAL AGENT AND THE ROLE OF VIRAL HEPARAN SULFATE BINDING REGIONS ON HSV ENDOCYTIC ENTRY AND FUSION
Washington State University
Doctor of Philosophy (PhD), Washington State University
01/2021
DOI:
https://doi.org/10.7273/000002387
Handle:
https://hdl.handle.net/2376/121783
Abstract
Herpes simplex virus (HSV) is a complex, significant pathogen that affects a majority of the globe. There is no cure nor effective vaccine currently available. Treatment relies on antivirals, primarily the nucleoside analogue acyclovir. Viruses resistant to acyclovir have developed and new therapies are needed. Targeting a cellular process instead of a viral process offers the attractive advantage of potentially avoiding the development of resistance. Targeting viral entry for intervention offers the advantage of potentially avoiding viral establishment of latency. HSV requires the proteasome for either pH-dependent endocytic entry or pH-neutral plasma membrane entry. HSV requires glycoproteins B, D, H, and L (gB, gD, gH/gL) for fusion with a cellular membrane. Glycoprotein C (gC) has been implicated in aiding the regulation of fusion via gB. Both gB and gC bind heparan sulfate (HS) on the cell surface. Here, we investigate two avenues of potential targets for intervention in HSV entry: 1) The proteasome inhibitor bortezomib and 2) the contribution of HS to viral entry and fusion. We show that 1) Bortezomib inhibits infection of HSV, including acyclovir-resistant strains at non-cytotoxic concentrations. We detail the mechanism of inhibition via capsid transport and disruption of cellular nuclear domain 10 (ND10) steps of infection. We show that bortezomib can act synergistically with acyclovir. We also show that 2) gC might play a role in preventing the accumulation of viral particles in endosomes, but that HS might not serve as an intermediary molecule between gB and gC in fusion and is not a determinant of entry route. We additionally show that heparin inhibition of fusion is unaffected by gC and the HS-binding region of gB. Overall, we propose a new option for combatting HSV infection and expand on insights in viral entry.
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Details
- Title
- MECHANISM AND SYNERGISTIC POTENTIAL OF BORTEZOMIB AS AN ANTIHERPESVIRAL AGENT AND THE ROLE OF VIRAL HEPARAN SULFATE BINDING REGIONS ON HSV ENDOCYTIC ENTRY AND FUSION
- Creators
- Seth Maxwell Schneider
- Contributors
- Anthony V Nicola (Advisor)Alan G Goodman (Committee Member)Robert H Mealey (Committee Member)Eric A Shelden (Committee Member)
- Awarding Institution
- Washington State University
- Academic Unit
- Molecular Biosciences, School of
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Publisher
- Washington State University
- Number of pages
- 140
- Identifiers
- 99900606651301842
- Language
- English
- Resource Type
- Dissertation