Replication Potential and Cell-tropism of Residual Plasma HIVs
残留血浆 HIV 的复制潜力和细胞向性
基本信息
- 批准号:8410803
- 负责人:
- 金额:$ 8.55万
- 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:2012-05-15 至 2014-04-30
- 项目状态:已结题
- 来源:
- 关键词:AdherenceAnti-Retroviral AgentsAntiretroviral resistanceAstrocytesBiologic CharacteristicBiological AssayCD34 geneCD4 Positive T LymphocytesCellsChronicClinicClinicalCloningDataDetectionDrug resistanceEvolutionFundingFutureGenetic MaterialsGenomeGoalsHIVHematopoieticImmuneIn VitroInfectionInterruptionKnowledgeLaboratoriesLengthLong-Term EffectsMethodsMinorMolecularMolecular CloningMutationNaturePatientsPharmaceutical PreparationsPlasmaPlayProductionProliferatingPublishingReagentRecoveryRelative (related person)ResearchResearch Project GrantsResidual stateRoleSatellite VirusesSourceStem cellsT-LymphocyteTechniquesTestingTropismUmbilical Cord BloodVariantViralViral GenomeViral Load resultViremiaVirionVirusVirus ReplicationWorkantiretroviral therapybasecell typeclinically significantdesigneffective therapyexpectationexperienceimmune activationin vivointerestmacrophagemonocytenovelnovel therapeuticsparticlestemtissue cultureviral DNA
项目摘要
DESCRIPTION (provided by applicant): In spite of prolonged, effective treatment using currently available antiretroviral therapy (ART), HIV replication continues at residual levels in patients, even below the detection limit (~50 vRNA copies per ml of plasma) of ultrasensitive clinical viral load assays. The clinical significance and the cellular source of this persistent residual viremia still remain unclear. Although residual viruses remain incapable of establishing productive infection in presence of ART, it is not clear whether they consist of genetic materials capable of producing infectious and replication-competent virus particles after therapy-interruption. If true, then the significance is that residual viruses could potentially contribute o the evolution of drug-resistance in patients during low-adherence to therapy and also spark rapid spreading of HIV when ART is discontinued. To investigate these possibilities, we have prepared this R03 application with the objectives to obtain knowledge about the replication potential, coreceptor usage and cell-tropism of residual plasma viruses present in patients on effective therapy. We will be testing two hypotheses in this application: the hypothesis 1 is that most RVs are replication-competent, and can infect and replicate readily in activated CD4 T cells in absence of ART, which we have formulated based on our preliminary data obtained from a patient on suppressive ART. The hypothesis-2 is about how residual virus can potentially establish a chronic reservoir and persist in an intrinsically stable and proliferating cell-type, perhaps in haematopoietic stem/progenitor cells of monocyte-macrophage lineage. This is formulated based on our and others published data in the field. To test our hypotheses and accomplish our overall objectives, we will pursue two specific aims: in Aim 1, we will clone residual viruses molecularly starting from residual plasma vRNAs using a novel method that we designed, and test the cloned viruses for their infectivity and coreceptor usage during infection of target cells in vitro. In Aim 2, we will determine replication potential of cloned residual virues in CD4 T cells, macrophages, CD34+ stem cells and primary astrocytes in vitro and compare with that of corresponding primary virus isolates from CD4 T cells, in order to help reveal the residual viruses' source in vivo. The rationale for the proposed research is that once we clone and characterize residual viruses phenotypically in vitro, we can put efforts to understand what role they play in drug resistance, viral load blips, persistent immune activation and sub-optimal immune recovery in patients on ART. It is our expectation that the proposed project will generate useful reagents and critical new information that will allow us to probe the clinical significance of low-level viremia during suppressive ART.
PUBLIC HEALTH RELEVANCE: The currently available antiretroviral therapy (ART) for HIV can reduce viral loads in patients to very low-levels (known as 'residual viremia') which remain undetectable even by the ultrasensitive viral load tests used in clinic, but are usually detectable
by more sensitive laboratory techniques. The studies proposed in this application are aimed at understanding of whether residual viremia has any clinical significance, by cloning residual viruses from patients using molecular techniques and testing them for various biological characteristics in laboratory tissue cultures. These studies should provide new knowledge that would be useful in designing new therapeutic strategies in future for complete inhibition of low-level HIV replication in patients on therapy.
描述(由申请方提供):尽管使用目前可用的抗逆转录病毒疗法(ART)进行了长期有效的治疗,但患者体内的HIV复制仍处于残留水平,甚至低于超灵敏临床病毒载量测定的检测限(约50 vRNA拷贝/ml血浆)。这种持续残留病毒血症的临床意义和细胞来源仍然不清楚。尽管残留病毒在ART存在下仍然不能建立生产性感染,但尚不清楚它们是否由能够在治疗中断后产生感染性和复制能力病毒颗粒的遗传物质组成。如果这是真的,那么重要的是,残留的病毒可能会在对治疗依从性低的患者中导致耐药性的演变,并且在ART停止时也会引发HIV的快速传播。为了研究这些可能性,我们准备了R 03申请,目的是获得关于接受有效治疗的患者中存在的残留血浆病毒的复制潜力、辅助受体使用和细胞嗜性的知识。我们将在此应用程序中测试两个假设:假设1是大多数RV具有复制能力,并且在没有ART的情况下可以在活化的CD 4 T细胞中容易地感染和复制,我们已经制定了基于我们的初步数据,从病人的抑制性艺术。假设-2是关于残余病毒如何能够潜在地建立慢性储库并持续存在于内在稳定和增殖的细胞类型中,可能存在于单核细胞-巨噬细胞谱系的造血干/祖细胞中。这是根据我们和其他人在该领域发表的数据制定的。为了验证我们的假设并实现我们的总体目标,我们将追求两个具体目标:在目标1中,我们将使用我们设计的新方法从残留的血浆vRNA开始分子克隆残留病毒,并测试克隆的病毒在体外感染靶细胞期间的感染性和辅助受体使用。目的二是通过体外实验检测克隆的残余病毒在CD 4 T细胞、巨噬细胞、CD 34+干细胞和原代星形胶质细胞中的复制能力,并与相应的原代分离株进行比较,以帮助揭示体内残余病毒的来源。这项研究的基本原理是,一旦我们在体外克隆和表征残留病毒的表型,我们就可以努力了解它们在耐药性、病毒载量波动、持续的免疫激活和亚我们期望所提出的项目将产生有用的试剂和关键的新信息,使我们能够探索其临床意义。在抑制性抗逆转录病毒治疗期间出现低水平病毒血症
公共卫生相关性:目前可用的HIV抗逆转录病毒疗法(ART)可以将患者的病毒载量降低到非常低的水平(称为“残留病毒血症”),即使通过临床上使用的超灵敏病毒载量测试也无法检测到,但通常可以检测到
更灵敏的实验室技术。本申请中提出的研究旨在通过使用分子技术从患者中克隆残留病毒并在实验室组织培养物中检测其各种生物学特性,了解残留病毒血症是否具有任何临床意义。这些研究应该提供新的知识,将是有用的,在未来设计新的治疗策略,完全抑制低水平的艾滋病毒复制的患者治疗。
项目成果
期刊论文数量(0)
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Gautam K. Sahu其他文献
Gautam K. Sahu的其他文献
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{{ truncateString('Gautam K. Sahu', 18)}}的其他基金
In-vitro model to recapitulate the natural HIV-1 latency
重现 HIV-1 自然潜伏期的体外模型
- 批准号:
8847162 - 财政年份:2015
- 资助金额:
$ 8.55万 - 项目类别:
Replication Potential and Cell-tropism of Residual Plasma HIVs
残留血浆 HIV 的复制潜力和细胞向性
- 批准号:
8465182 - 财政年份:2012
- 资助金额:
$ 8.55万 - 项目类别:
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