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dc.contributor.authorCallaway, Heather
dc.date.accessioned2018-10-23T13:34:27Z
dc.date.available2020-08-22T06:00:27Z
dc.date.issued2018-08-30
dc.identifier.otherCallaway_cornellgrad_0058F_10895
dc.identifier.otherhttp://dissertations.umi.com/cornellgrad:10895
dc.identifier.otherbibid: 10489729
dc.identifier.urihttps://hdl.handle.net/1813/59633
dc.description.abstractParvoviruses are among the simplest of viruses, with capsids composed of variants of a single structural protein. These capsids mediate many of the processes required for infection and are remarkably stable. However, antibody binding or mutations to the capsid can disrupt these processes and block infection. This dissertation discusses mutations to the canine parvovirus (CPV) capsid that result in loss of infection, the interaction between CPV and the transferrin receptor (TfR), and parvovirus endogenous viral elements (EVEs), which contain ancient parvovirus gene sequences. I found that point mutations to CPV VP2 residues 270, 272, 273, and 299/300 result in loss of viral infectivity. Mutation of residue 270 results in loss of a sub-molar proteolytic cleavage event in VP2 and increases capsid stability, residue 272 mutation causes loss of capsid assembly, and residue 273 mutation results in assembled capsids being trapped in the nucleus. Mutation of VP2 residues 299 and 300, which are associated with TfR binding, to lysine disrupts the interaction between CPV and the TfR, inhibiting infection but still allowing receptor binding and uptake into cells. I also found that CPV has different interactions with TfRs from different host species, binding strongly to some TfRs and very weakly to others, even though each TfR can mediate a successful infection. TfRs from different species also had varying levels of occupancy on CPV capsids, with up to 12 black-backed jackal TfRs, but only 1-2 feline TfRs binding to each capsid, and it is possible that the feline TfR induces a conformational change in CPV that inhibits binding of additional TfRs. Antibody binding could also disrupt the CPV/TfR binding interaction, suggesting a possible mechanism of virus neutralization. To examine the structure and function of ancient parvovirus capsids, I expressed the VP2 gene from three different parvovirus EVEs. VP2 expressed from an EVE in the M. spretus genome assembled into capsids, and I determined that these capsids were highly stable, could bind to N-Acetylneuraminic acid, and were endocytosed into murine cells. The results in this dissertation provide new information about parvovirus infection, receptor binding interactions, and evolution, and further the understanding of how infection occurs and may be disrupted.
dc.language.isoen_US
dc.subjectBiophysics
dc.subjectBiochemistry
dc.subjectcanine parvovirus
dc.subjectendogenous viral element
dc.subjectparvovirus
dc.subjectreceptor binding
dc.subjecttransferrin receptor
dc.subjectvirus structure
dc.subjectVirology
dc.titlePARVOVIRUS CAPSID STRUCTURES, LIGAND BINDING INTERACTIONS, AND ENDOGENOUS VIRAL ELEMENTS
dc.typedissertation or thesis
thesis.degree.disciplineImmunology and Infectious Disease
thesis.degree.grantorCornell University
thesis.degree.levelDoctor of Philosophy
thesis.degree.namePh. D., Immunology and Infectious Disease
dc.contributor.chairParrish, Colin Ross
dc.contributor.committeeMemberWhittaker, Gary R.
dc.contributor.committeeMemberNicholson, Linda K.
dc.contributor.committeeMemberWagner, Bettina
dcterms.licensehttps://hdl.handle.net/1813/59810
dc.identifier.doihttps://doi.org/10.7298/X4DZ06J9


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