Matches in SemOpenAlex for { <https://semopenalex.org/work/W2298045296> ?p ?o ?g. }
Showing items 1 to 80 of
80
with 100 items per page.
- W2298045296 abstract "Resistance to combined antiretroviral therapy (cART) in HIV-1 infected individuals is typically due to non-synonymous mutations that change the protein sequence; however, the selection of synonymous or ‘silent’ mutations in the HIV-1 genome with cART has been reported. These silent K65K and K66K mutations in the HIV-1 reverse transcriptase (RT) occur in over 35% of drug-experienced individuals and are highly associated with the thymidine analog mutations (TAMs) D67N and K70R, which confer decreased susceptibility to most HIV-1 nucleoside/nucleotide RT inhibitor drugs. However, the basis for the selection of these silent mutations under drug pressure and their role in HIV-1 replication are unknown. Introduction of either K65K or K66K into HIV-1 containing D67N/K70R improved viral replication fitness but did not impact RT inhibitor drug susceptibility. Using Illumina next- generation sequencing, it is demonstrated that D67N/K70R substitutions in HIV-1 RT increase indel frequency by 100-fold at RT codons 65-67, consequently impairing viral fitness. The fitness advantage conferred by K65K/K66K is likely due to their ability to alleviate decreased RT efficiency on homopolymeric stretches of nucleotides and reverse the introduction of indels due to the emergence of TAMs. A retrospective population analysis of the British Columbia cohort revealed that these silent mutations were increasing in prevalence in drug-naive individuals. Additionally, K65K and K66K emerge in antiretroviral drug treated patients in the absence of TAMs in over 13% of the cohort analysed, suggesting there may be a role for these silent mutations independent of TAMs. In this regard, preliminary data suggest that neither K65K nor K66K are likely to be deleterious in the context of wild type virus. A parallel investigation of the role of homopolymeric stretches of nucleotides in the HIV-1 genome in regions distinct from the RT coding region revealed that an extended stretch of iterated sequence can result in virus fitness defects relative to wild type. These studies suggest that the emergence of a silent mutation to disrupt this homopolymeric stretch could restore viral fitness. Taken together, this study has demonstrated that the silent mutations can act as compensatory mutations to alleviate defects conferred by D67N and K70R. These data provide new mechanistic insights into the role of silent mutations selected during cART and have broader implications for the relevance of silent mutations in the evolution and fitness of RNA viruses." @default.
- W2298045296 created "2016-06-24" @default.
- W2298045296 creator A5055513726 @default.
- W2298045296 date "2017-02-27" @default.
- W2298045296 modified "2023-09-27" @default.
- W2298045296 title "Role of silent mutations K65K and K66K in subtype B HIV-1 reverse transcriptase selected during drug therapy" @default.
- W2298045296 doi "https://doi.org/10.4225/03/58b38aba7d9e9" @default.
- W2298045296 hasPublicationYear "2017" @default.
- W2298045296 type Work @default.
- W2298045296 sameAs 2298045296 @default.
- W2298045296 citedByCount "0" @default.
- W2298045296 crossrefType "dissertation" @default.
- W2298045296 hasAuthorship W2298045296A5055513726 @default.
- W2298045296 hasConcept C104317684 @default.
- W2298045296 hasConcept C114851261 @default.
- W2298045296 hasConcept C119054055 @default.
- W2298045296 hasConcept C127413603 @default.
- W2298045296 hasConcept C135763542 @default.
- W2298045296 hasConcept C153209595 @default.
- W2298045296 hasConcept C156719811 @default.
- W2298045296 hasConcept C159047783 @default.
- W2298045296 hasConcept C182707283 @default.
- W2298045296 hasConcept C195491092 @default.
- W2298045296 hasConcept C2777275308 @default.
- W2298045296 hasConcept C2908647359 @default.
- W2298045296 hasConcept C49105822 @default.
- W2298045296 hasConcept C501734568 @default.
- W2298045296 hasConcept C54355233 @default.
- W2298045296 hasConcept C71924100 @default.
- W2298045296 hasConcept C75563809 @default.
- W2298045296 hasConcept C78519656 @default.
- W2298045296 hasConcept C86803240 @default.
- W2298045296 hasConcept C99454951 @default.
- W2298045296 hasConceptScore W2298045296C104317684 @default.
- W2298045296 hasConceptScore W2298045296C114851261 @default.
- W2298045296 hasConceptScore W2298045296C119054055 @default.
- W2298045296 hasConceptScore W2298045296C127413603 @default.
- W2298045296 hasConceptScore W2298045296C135763542 @default.
- W2298045296 hasConceptScore W2298045296C153209595 @default.
- W2298045296 hasConceptScore W2298045296C156719811 @default.
- W2298045296 hasConceptScore W2298045296C159047783 @default.
- W2298045296 hasConceptScore W2298045296C182707283 @default.
- W2298045296 hasConceptScore W2298045296C195491092 @default.
- W2298045296 hasConceptScore W2298045296C2777275308 @default.
- W2298045296 hasConceptScore W2298045296C2908647359 @default.
- W2298045296 hasConceptScore W2298045296C49105822 @default.
- W2298045296 hasConceptScore W2298045296C501734568 @default.
- W2298045296 hasConceptScore W2298045296C54355233 @default.
- W2298045296 hasConceptScore W2298045296C71924100 @default.
- W2298045296 hasConceptScore W2298045296C75563809 @default.
- W2298045296 hasConceptScore W2298045296C78519656 @default.
- W2298045296 hasConceptScore W2298045296C86803240 @default.
- W2298045296 hasConceptScore W2298045296C99454951 @default.
- W2298045296 hasLocation W22980452961 @default.
- W2298045296 hasOpenAccess W2298045296 @default.
- W2298045296 hasPrimaryLocation W22980452961 @default.
- W2298045296 hasRelatedWork W2009419809 @default.
- W2298045296 hasRelatedWork W2014637732 @default.
- W2298045296 hasRelatedWork W2020014483 @default.
- W2298045296 hasRelatedWork W2022259265 @default.
- W2298045296 hasRelatedWork W2024731636 @default.
- W2298045296 hasRelatedWork W2041335447 @default.
- W2298045296 hasRelatedWork W2045092579 @default.
- W2298045296 hasRelatedWork W2073200892 @default.
- W2298045296 hasRelatedWork W2084231823 @default.
- W2298045296 hasRelatedWork W2094661145 @default.
- W2298045296 hasRelatedWork W2096969333 @default.
- W2298045296 hasRelatedWork W2111904018 @default.
- W2298045296 hasRelatedWork W2122621859 @default.
- W2298045296 hasRelatedWork W2123090801 @default.
- W2298045296 hasRelatedWork W2130244472 @default.
- W2298045296 hasRelatedWork W2151501700 @default.
- W2298045296 hasRelatedWork W2151989745 @default.
- W2298045296 hasRelatedWork W2159526063 @default.
- W2298045296 hasRelatedWork W2414255386 @default.
- W2298045296 hasRelatedWork W2593709699 @default.
- W2298045296 isParatext "false" @default.
- W2298045296 isRetracted "false" @default.
- W2298045296 magId "2298045296" @default.
- W2298045296 workType "dissertation" @default.