The research for this doctoral dissertation was undertaken to: (1)establish a rationale that is supported by published laboratory and clinical data for prospective clinical investigation of the therapeutic maintenance of the M184V mutation in human immunodeficiency virus type-1 (HIV-1) reverse transcriptase (RT) in antiretroviral therapy-experienced patients with virological failure, and, (2)to study the relative effectiveness of various nucleoside analogue reverse transcriptase inhibitors (NRTIs) that are structurally-unrelated to 3TC in selecting and/or maintaining M184V in tissue culture and whether continuous exposure to therapeutic levels of 3TC is the only means of attaining this objective. Accordingly, we have evaluated the ability of zalcitabine (D.C.), didanosine (ddI), abacavir (ABC) and the novel nucleoside analogue SPD754, in addition to 3TC, to maintain the presence of M184V in tissue culture and have shown that each of SPD754, ABC and 3TC were able to preserve M184V in mixed dual infections consisting of wild-type viruses and clinical isolates in which the M184V mutation was present either alone or in a genetic background consisting of several other resistance-conferring mutations in the RT gene. Moreover, M184V could also be maintained in these cultures when a subtherapeutic concentration of 3TC (i.e., 0.05 muM) was used. In contrast, neither ddI nor D.C. were able to maintain M184V to the same extent as the other drugs tested after up to ten weeks of tissue culture in mixtures of wild-type viruses and isolates containing only M184V, especially when the latter represented a minority species in the viral population. The M184V substitution in HIV-1 RT develops rapidly following initiation of therapy with 3TC and confers high-level phenotypic resistance to this drug and a related analogue, FTC, both in vitro and in vivo. Interestingly, the proximity of the M184V mutation in relation to the polymerase active site is also respons
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.85952 |
| Date | January 2005 |
| Creators | Petrella, Marco |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Division of Experimental Medicine.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 002261158, proquestno: AAINR21689, Theses scanned by UMI/ProQuest. |
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