HIV entry : a biophysical and mutational analysis of gp41-mediated membrane fusion and its inhibition
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2005.
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| Format: | Thesis |
| Language: | eng |
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Massachusetts Institute of Technology
2006
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| Online Access: | http://hdl.handle.net/1721.1/31181 |
| _version_ | 1826213610489118720 |
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| author | Suntoke, Tara R |
| author2 | Peter S. Kim and David C. Chan. |
| author_facet | Peter S. Kim and David C. Chan. Suntoke, Tara R |
| author_sort | Suntoke, Tara R |
| collection | MIT |
| description | Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2005. |
| first_indexed | 2024-09-23T15:51:59Z |
| format | Thesis |
| id | mit-1721.1/31181 |
| institution | Massachusetts Institute of Technology |
| language | eng |
| last_indexed | 2024-09-23T15:51:59Z |
| publishDate | 2006 |
| publisher | Massachusetts Institute of Technology |
| record_format | dspace |
| spelling | mit-1721.1/311812019-04-12T09:52:24Z HIV entry : a biophysical and mutational analysis of gp41-mediated membrane fusion and its inhibition Biophysical and mutational analysis of gp41-mediated membrane fusion and its inhibition Suntoke, Tara R Peter S. Kim and David C. Chan. Massachusetts Institute of Technology. Dept. of Biology. Massachusetts Institute of Technology. Dept. of Biology. Biology. Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2005. Includes bibliographical references. The experiments described in this thesis were designed to elucidate the manner in which the HIV-1 envelope protein (Env) initiates infection of host cells, and to develop inhibitors of viral entry. Env comprises two non-covalently attached subunits, gpl20 and gp41, that associate as a trimer on the virion surface. Once gp 120 contacts the target cell, gp41 undergoes extensive conformational changes to mediate fusion of viral and cellular membranes. First, a short hydrophobic stretch of residues at the gp4 1 N-terminus insert into the target membrane, anchoring the protein in both viral and cellular membranes. This 'prehairpin' intermediate structure exposes an N-terminal a-helical coiled coil that is the target of promising antiviral peptides and small molecules. A previously unstudied region of N-terminal trimer was stabilized by fusion to a trimeric scaffold peptide and biophysically characterized (Chapter 2). This hybrid peptide itself potently inhibited HIV fusion, and the basis for this inhibition was assessed by studying mutant molecules. Efforts to use this peptide as an immunogen to elicit anti-gp41 antibodies are also outlined. Similar design strategies may be useful in developing N-terminal peptide inhibitors and HIV vaccine candidates, and in screening for antiviral molecules that bind to this region. As fusion progresses, the prehairpin intermediate resolves into a hairpin structure. This critical transition involves interaction of the N-terminal coiled coil with the gp41 C-terminal region. Evidence suggests that this N-C association provides the energy necessary to promote juxtaposition and merging of viral and cellular membranes. (cont.) This hypothesis was tested using a biophysical and cell biological approach (Chapter 3), in which residues essential for this transition were mutated and analyzed. These studies confirm the hypothesis and highlight the importance of specific hydrophobic and polar contacts between the N- and C- terminal gp41 regions. This work contributes to a detailed understanding of the gp41 fusion machinery; furthermore, it shows that such knowledge can be used to design effective viral entry inhibitors. Finally, Chapter 4 places this work in the context of a broad overview of current drug and vaccine developments, and addresses some of the significant challenges that confront HIV researchers. by Tara R. Suntoke. Ph.D. 2006-02-02T18:56:14Z 2006-02-02T18:56:14Z 2005 2005 Thesis http://hdl.handle.net/1721.1/31181 61267186 eng M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission. http://dspace.mit.edu/handle/1721.1/7582 114 leaves 6240695 bytes 6254745 bytes application/pdf application/pdf application/pdf Massachusetts Institute of Technology |
| spellingShingle | Biology. Suntoke, Tara R HIV entry : a biophysical and mutational analysis of gp41-mediated membrane fusion and its inhibition |
| title | HIV entry : a biophysical and mutational analysis of gp41-mediated membrane fusion and its inhibition |
| title_full | HIV entry : a biophysical and mutational analysis of gp41-mediated membrane fusion and its inhibition |
| title_fullStr | HIV entry : a biophysical and mutational analysis of gp41-mediated membrane fusion and its inhibition |
| title_full_unstemmed | HIV entry : a biophysical and mutational analysis of gp41-mediated membrane fusion and its inhibition |
| title_short | HIV entry : a biophysical and mutational analysis of gp41-mediated membrane fusion and its inhibition |
| title_sort | hiv entry a biophysical and mutational analysis of gp41 mediated membrane fusion and its inhibition |
| topic | Biology. |
| url | http://hdl.handle.net/1721.1/31181 |
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