DNA deaminases and HIV drug resistance
DNA 脱氨酶和 HIV 耐药性
基本信息
- 批准号:8463411
- 负责人:
- 金额:$ 2.8万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-04-01 至 2015-03-31
- 项目状态:已结题
- 来源:
- 关键词:AIDS/HIV problemAddressAdverse effectsAffectAnti-Retroviral AgentsAntiviral AgentsCell LineCharacteristicsChemicalsComplementary DNAConsensusCytosineCytosine deaminaseDNADNA-Directed DNA PolymeraseDataDeaminaseDeaminationDependencyDevelopmentDrug resistanceDrug userEnzymesExhibitsFamilyFamily memberFigs - dietaryFutureGenesGenetic VariationHIVHIV drug resistanceHost DefenseHumanImmuneIndividualLeadMediatingMutagenesisMutationPatientsPharmaceutical PreparationsPhenotypePopulationPopulations at RiskProteinsRNA-Directed DNA PolymeraseRelative (related person)ResistanceReverse TranscriptionRiskRoleSourceT-LymphocyteTechnologyTestingTranscriptTreatment ProtocolsUracilViralViral Drug ResistanceViral ProteinsVirusVirus DiseasesWorkapolipoprotein B mRNA editing enzymebasedrug resistant viruseffective therapyin vivointravenous drug usermembernext generation sequencingnovelnovel therapeuticspolypeptidepublic health relevancesubstance abusertherapy developmenttransition mutationviral DNAvirus genetics
项目摘要
DESCRIPTION (provided by applicant): HIV lacking Vif is susceptible to human APOBEC3 (A3)-mediated restriction, rendering the virus non-infectious. The archetypal family member, A3G, has a well-defined role in HIV restriction in T cells. Other A3s have been implicated but despite nearly a decade of study, no consensus has been reached regarding the restrictive repertoire. Following reverse transcription, nascent viral cDNA transcripts are deaminated by A3 proteins resulting in transition mutations that inhibit HIV replication. To counteract this, Vif targets A3s for proteolytic degradation. However, sequences derived from infected patients exhibit G-to-A hypermutation, a hallmark of A3 activity, suggesting Vif neutralization in vivo is incomplete. I hypothesize that these mutations promote HIV genetic variation and underlie beneficial phenotypes such as the acquisition of drug resistance. In the following proposal, I will
define three vital characteristics of the A3 family: (i) which A3s are relevant to HIV restriction,(ii) the extent to which they contribute to the HIV mutation rate, and, (iii) whether drug-resistant virl isolates emerge following A3-mediated sub-lethal mutagenesis. I anticipate that when taken together these studies will supply definitive conclusions to the innate host-defense field while prioritizing efforts to develop future HIV/AIDS therapies especially for HIV infected substance abusers.
描述(由申请人提供):缺乏VIF的艾滋病毒易受人类Apobec3(A3)介导的限制,使病毒不感染。原型家庭成员A3G在T细胞中在HIV限制中起着明确的作用。其他A3也被牵涉到,但尽管研究了将近十年,但尚未就限制性曲目达成共识。逆转录后,新生的病毒cDNA转录本被A3蛋白脱氨,导致抑制HIV复制的转变突变。为了抵消这一点,VIF靶向蛋白水解降解的A3S。然而,从感染患者中得出的序列表现出G-TO-A超成名,这是A3活性的标志,表明体内VIF中和不完全。我假设这些突变促进了HIV遗传变异和基础有益表型,例如获得耐药性。在以下建议中,我将
定义A3家族的三个重要特征:(i)A3与HIV限制相关,(ii)它们对HIV突变率的贡献程度,以及(iii)在A3介导的亚lettletlethal ure型后,(iii)是否会出现抗药性抗性分离株。我预计,当共同完成这些研究时,这些研究将为先天的宿主防御领域提供明确的结论,同时优先考虑开发未来的艾滋病毒/艾滋病疗法,尤其是针对艾滋病毒感染的滥用药物。
项目成果
期刊论文数量(0)
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Eric Refsland其他文献
Eric Refsland的其他文献
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