dc.contributor.advisor | Sarafianos, Stefan G. | eng |
dc.contributor.author | Flores, Jacqueline A. | eng |
dc.date.issued | 2017 | eng |
dc.date.submitted | 2017 Spring | eng |
dc.description.abstract | [ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT REQUEST OF AUTHOR.] Two classes of drugs: nucleos(t)ide reverse transcriptase inhibitors (NRTIs) and non-nucleoside RT inhibitors (NNRTIs) target HIV-1 RT, an enzyme required for HIV replication. The first generation NNRTIs (nevirapine and efavirenz) have been extensively used worldwide. However, they have a low genetic barrier for resistance. The second generation NNRTI, Rilpivirine (RPV) is effective against viruses that are resistant to nevirapine and efavirenz. RPV has not been used against subtype C HIV-1, which accounts for [about]50% of all infections. Recent clinical trials have shown that patients with subtype C are more likely to fail RPV-based treatment. However, the mechanism of RPV-failure has not been determined. To get insight into RPV-failure, RTs from patient isolates were cloned and biochemically characterized using pre-steady state kinetics to determine: 1) the impact of genetic variation on HIV-1 replication, and 2) the effect of a known RPVresistance mutation (p66E138K-M184I/p51E138K) on the initiation of reverse transcription, the first step of HIV replication. The results showed that subtype C HIV-1 RT has lower DNA and dNTP binding affinities, and RPV binding affinity than subtype B HIV-1 RT. The p66E138K-M184I/p51E138K mutation was found to cause rilpivirine to dissociate from p66E138KM184I/p51E138K RT 3x faster than wild type RT at initiation suggesting that RPV may not be an optimal choice for that subtype C infections. | eng |
dc.identifier.uri | https://hdl.handle.net/10355/62017 | |
dc.language | English | eng |
dc.publisher | University of Missouri--Columbia | eng |
dc.relation.ispartofcommunity | University of Missouri--Columbia. Graduate School. Theses and Dissertations | eng |
dc.rights | Access is limited to the University of Missouri--Columbia | eng |
dc.source | Submitted by the University of Missouri--Columbia Graduate School. | eng |
dc.subject.FAST | Reverse transcriptase | eng |
dc.subject.FAST | Drug resistance | eng |
dc.subject.FAST | HIV (Viruses) | eng |
dc.title | Biochemical characterization of clade B and non-B HIV-1 reverse transcriptase | eng |
dc.type | Thesis | eng |
thesis.degree.discipline | Microbiology (Medicine) (MU) | eng |
thesis.degree.grantor | University of Missouri--Columbia | eng |
thesis.degree.level | Masters | eng |
thesis.degree.name | M.S. | eng |