Characterization of Non-subtype B HIV-1 Reservoirs and its Association with Longitudinal Clinical Outcomes
非 B 亚型 HIV-1 病毒库的特征及其与纵向临床结果的关系
基本信息
- 批准号:10327111
- 负责人:
- 金额:$ 43.79万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-06-01 至 2026-05-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAffectAfrica South of the SaharaAnti-Retroviral AgentsAntiviral AgentsArchivesBase PairingBinding SitesBioinformaticsBiological AssayBlood CellsCD4 Lymphocyte CountCXCR4 geneCellsCharacteristicsChromatinChronicClinicalClonal ExpansionCommunitiesDNADataDatabasesDemographic FactorsEpidemicFrequenciesFundingGenesGenetic TranscriptionGenetic VariationGenomeGenotypeHIVHIV GenomeHIV InfectionsHIV antiretroviralHIV-1ImmuneIndividualInfectionIntegration Host FactorsInterruptionLeadLengthLinkMeasuresMutateMutationOutcomePatientsPlasmaPrincipal InvestigatorPromoter RegionsPropertyProvirusesRNA SequencesRefractoryResearchSamplingTechnologyTherapeutic EffectTimeTranscriptional ActivationUnited States National Institutes of HealthVariantViralViral GenomeViral reservoirViremiaVirusVirus IntegrationVirus LatencyVirus Replicationactivating transcription factorantiretroviral therapybasebiobankbiological sexburden of illnesscohorthuman DNAintegration sitemortalitypromoterreceptorviral DNAviral RNAviral reboundvirologywhole genome
项目摘要
PROJECT SUMMARY
Current HIV antiretroviral treatment successfully controls viral replication and has transformed HIV-infection from
a fatal illness to a manageable chronic condition. However, despite suppression of viral replication during
treatment, studies have shown that pools of latent viral reservoirs remain detectable, which fuel viral rebound
when antiviral suppression treatment is interrupted. These viral reservoirs are established almost immediately
upon infection when HIV irreversibly integrates its viral genome into human DNA. Viral reservoirs are extremely
durable, not susceptible to therapeutic effects of currently available antiretroviral agents, and have been
refractory to recent experimental treatment approaches. HIV infection is also characterized by a high level of
intrahost genotypic diversity of viral quasispecies. In addition to genetic diversity associated base substitution
mutations, pools of viral DNA genomes recovered from chronically-infected patients under prolonged
suppressive therapy often contain high frequencies of genome-truncated and/or hypermutated, non-replication-
competent viral DNA genomes. Only a small fraction of proviral genomes in these patients are genome-intact
and may lead to productive viral replication and virologic rebound in the absence of treatment. Furthermore,
HIV-infected cells infected with both genome-intact and genome-defective proviruses have been shown to
clonally expand, serving as a mechanism of HIV persistence. However, our current understanding of HIV
reservoirs has been derived almost exclusively from studies on a strain called subtype B HIV-1, the predominate
viral subtype affecting first-world nations but only makes up 10% of the global epidemic. In contrast, non-B HIV-
1 subtypes predominate regions such as sub-Saharan Africa where disease burden is the highest globally.
Questions remain on whether the remaining 90% of infections by other HIV-1 subtypes differ in reservoir sizes
and compositions. To address this question, we will leverage an existing biobank of a previously NIH-funded
Ugandan HIV cohort (UARTO), which houses 12360 blood cell samples collected longitudinally over ten years
from 500 predominantly subtype A1 and D HIV-1-infected individuals. We will use three cutting-edge
technologies (1) FLIP-seq to obtain near-full-length HIV-1 DNA genomes profiles, (2) MIP-seq to co-capture HIV-
1 integration sites and viral genome, and (3) and the Intact Proviral DNA Assay (IPDA) to longitudinally measure
the decay/expansion rate of the reservoir. All three technologies allow us to focus on the rare intact viral DNA
genomes that is the target for HIV cure strategies. Across subtypes, we will compare reservoir characteristics
including absolute genome-intact reservoir sizes, extent of clonal expansion, integration site profiles, viral
promoter genotypes, and longitudinal decay/expansion dynamics. We will further investigate demographic,
clinical and host factors associated with genome-intact viruses. Overall, we aim identify differences, or the lack
of differences, between HIV-1 subtype reservoirs to inform HIV cure research effort on whether a cure strategy
should be subtype-specific.
项目概要
目前的艾滋病毒抗逆转录病毒治疗成功地控制了病毒复制,并已将艾滋病毒感染从
致命的疾病转变为可控制的慢性病。然而,尽管病毒复制受到抑制
研究表明,潜伏病毒库仍然可以检测到,这会加剧病毒反弹
当抗病毒抑制治疗中断时。这些病毒库几乎立即建立
感染后,HIV 不可逆地将其病毒基因组整合到人类 DNA 中。病毒储存库极为
持久,不易受到现有抗逆转录病毒药物治疗效果的影响,并且已被
对最近的实验性治疗方法无效。 HIV感染的另一个特点是高水平
病毒准种的宿主内基因型多样性。除了与碱基取代相关的遗传多样性
突变,从长期感染的患者体内恢复的病毒 DNA 基因组池
抑制疗法通常包含高频率的基因组截短和/或超突变、非复制-
有效的病毒DNA基因组。这些患者中只有一小部分原病毒基因组是完整的
在没有治疗的情况下,可能会导致有效的病毒复制和病毒学反弹。此外,
感染了基因组完整和基因组缺陷原病毒的 HIV 感染细胞已被证明
克隆扩展,作为艾滋病毒持续存在的机制。然而,我们目前对艾滋病毒的了解
病毒储存库几乎完全源自对一种称为 B 亚型 HIV-1 的毒株的研究,该毒株是主要的病毒株。
病毒亚型影响第一世界国家,但仅占全球流行病的 10%。相比之下,非 B HIV-
1 亚型在撒哈拉以南非洲等地区占主导地位,这些地区的疾病负担是全球最高的。
剩下的 90% 的其他 HIV-1 亚型感染的病毒库大小是否存在差异仍然存在疑问
和组合物。为了解决这个问题,我们将利用先前由 NIH 资助的现有生物库
乌干达 HIV 队列 (UARTO),包含 10 年来纵向收集的 12360 个血细胞样本
来自 500 名主要感染 A1 和 D 亚型 HIV-1 的个体。我们将使用三个尖端技术
技术 (1) FLIP-seq 获得接近全长的 HIV-1 DNA 基因组图谱,(2) MIP-seq 共同捕获 HIV-
1 整合位点和病毒基因组,以及 (3) 和完整原病毒 DNA 检测 (IPDA) 进行纵向测量
储层的衰减/膨胀率。所有这三种技术使我们能够专注于罕见的完整病毒 DNA
基因组是艾滋病毒治疗策略的目标。跨亚型,我们将比较储层特征
包括绝对基因组完整的储存库大小、克隆扩增的程度、整合位点概况、病毒
启动子基因型和纵向衰减/扩展动力学。我们将进一步调查人口统计、
与基因组完整病毒相关的临床和宿主因素。总的来说,我们的目标是找出差异或缺乏
HIV-1 亚型储存者之间的差异,为 HIV 治疗研究工作提供治疗策略是否可行的信息
应该是特定于子类型的。
项目成果
期刊论文数量(0)
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Kwun Wing Guinevere Lee其他文献
Kwun Wing Guinevere Lee的其他文献
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{{ truncateString('Kwun Wing Guinevere Lee', 18)}}的其他基金
Characterization of Non-subtype B HIV-1 Reservoirs and its Association with Longitudinal Clinical Outcomes
非 B 亚型 HIV-1 病毒库的特征及其与纵向临床结果的关系
- 批准号:
10643834 - 财政年份:2021
- 资助金额:
$ 43.79万 - 项目类别:
Characterization of Non-subtype B HIV-1 Reservoirs and its Association with Longitudinal Clinical Outcomes
非 B 亚型 HIV-1 病毒库的特征及其与纵向临床结果的关系
- 批准号:
10412140 - 财政年份:2021
- 资助金额:
$ 43.79万 - 项目类别:
Insights into the dynamics of clonal expansion of genome-intact proviruses by examining longitudinal evolution of HIV proviral DNA compositions
通过检查 HIV 原病毒 DNA 组成的纵向进化,深入了解基因组完整的原病毒克隆扩增的动态
- 批准号:
10013710 - 财政年份:2020
- 资助金额:
$ 43.79万 - 项目类别:
Insights into the dynamics of clonal expansion of genome-intact proviruses by examining longitudinal evolution of HIV proviral DNA compositions
通过检查 HIV 原病毒 DNA 组成的纵向进化,深入了解基因组完整的原病毒克隆扩增的动态
- 批准号:
10113528 - 财政年份:2020
- 资助金额:
$ 43.79万 - 项目类别:
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