| dc.contributor |
Vincent Hilser , PhD |
|
| dc.contributor |
Andres Oberhauser , PhD |
|
| dc.contributor |
James C . Lee , PhD |
|
| dc.contributor |
Wlodek Bujalowski , PhD |
|
| dc.contributor |
Alan D . T . Barrett , PhD |
|
| dc.contributor |
Hiram Gilbert , PhD |
|
| dc.creator |
Maillard , Rodrigo Alejandro |
|
| dc.date |
2009 -06 -09 |
|
| dc.date.accessioned |
2011 -04 -27T21 :39 :05Z |
|
| dc.date.available |
2011 -04 -27T21 :39 :05Z |
|
| dc.date.issued |
2011 -04 -27T21 :39 :05Z |
|
| dc.identifier |
http : / /etd .utmb .edu /theses /available /etd -03262007 -173222 / |
|
| dc.identifier.uri |
http : / /hdl .handle .net /2249 .1 /35773 |
|
| dc.description |
In order to establish infection , flaviviruses induce mutations in antigenic proteins as a strategy to evade neutralizing antibodies ; a phenomenon known as antibody -mediated neutralization resistance . Most of the critical mutations associated with antibody resistance are located in the envelope protein domain 3 (ED3 ) . In West Nile virus (WNV ) , and in other flaviviruses , mutations in ED3 are found throughout its structure , including regions outside of the viral epitope and /or not accessible to antibodies . Besides the trivial effects of local perturbations due to mutations in the epitope , these observations are consistent with our hypothesis that there is long -range communication connecting distant residues linked to the viral epitope . Mutations at sites distant but coupled to the epitope would lead to an alteration of affinity to antibody ; e .g . , resistance to antibody -mediated neutralization . In support of our hypothesis , we demonstrated by multiple biophysical approaches the communications among distant sites and a network of communications of energetically coupled residues . Within this network , mutations in WNV ED3 caused perturbations only in the loop connecting strands B -C (BC loop ) by changing the magnitude of energetic coupling between these distant sites . The magnitude of perturbation conveyed by the mutations is represented by a Boltzmann distribution . This suggests that neutralization resistance is the manifestation of an equilibrium process governing the distribution between ED3 conformations that are responsible for antibody neutralization -resistance and nonresistance . Indeed we observed a linear correlation between affinity for antibody and magnitude of energetic coupling on the BC loop . To test the generality of these results , we investigated the ED3 from dengue virus type 2 (DENV2 ) , a related flavivirus . We found that only the FG loop was susceptible to mutational perturbations . Remarkably , the BC and FG loops have been shown to be the dominant epitopes in ED3 for WNV and DENV2 , respectively . Evidently these distant sites are energetically coupled to their respective viral epitope . This study reveals the strategy by which flavivirus employed to evade antibody , namely , establishment of long -range communications in viral proteins to expand the mutational repertoire to perturb the epitopes and lower the affinity for antibodies resulting in evasion of antibody -mediated neutralization . |
|
| dc.format |
application /pdf |
|
| dc.language |
en |
|
| dc.publisher |
UTMB |
|
| dc.rights |
restricted |
|
| dc.rights |
I hereby certify that , if appropriate , I have obtained and attached hereto a written permission statement from the owner (s ) of each third party copyrighted matter to be included in my thesis , dissertation , or project report , allowing distribution as specified below . I certify that the version I submitted is the same as that approved by my advisory committee . I hereby grant to University of Texas Medical Branch or its agents the non -exclusive license to archive and make accessible , under the conditions specified below , my thesis , dissertation , or project report in whole or in part in all forms of media , now or hereafter known . I retain all other ownership rights to the copyright of the thesis , dissertation or project report . I also retain the right to use in future works (such as articles or books ) all or part of this thesis , dissertation , or project report . |
|
| dc.source |
http : / /etd .utmb .edu /theses /available /etd -03262007 -173222 / |
|
| dc.subject |
Human Biological Chemistry and Genetics |
|
| dc.title |
THE MOLECULAR BASIS FOR EVASION OF ANTIBODY -MEDIATED NEUTRALIZATION IN FLAVIVIRUSES |
|
| dc.type |
text |
|