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: 10327111
• 负责人: Kwun Wing Guinevere Lee
• 金额: $ 43.79万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10327111
• 关键词: Address; Affect; Africa South of the Sahara; Anti-Retroviral Agents; Antiviral Agents; Archives; Base Pairing; Binding Sites; Bioinformatics; Biological Assay; Blood Cells; CD4 Lymphocyte Count; CXCR4 gene; Cells; Characteristics; Chromatin; Chronic; Clinical; Clonal Expansion; Communities; DNA; Data; Databases; Demographic Factors; Epidemic; Frequencies; Funding; Genes; Genetic Transcription; Genetic Variation; Genome; Genotype; HIV; HIV Genome; HIV Infections; HIV antiretroviral; HIV-1; Immune; Individual; Infection; Integration Host Factors; Interruption; Lead; Length; Link; Measures; Mutate; Mutation; Outcome; Patients; Plasma; Principal Investigator; Promoter Regions; Property; Proviruses; RNA Sequences; Refractory; Research; Sampling; Technology; Therapeutic Effect; Time; Transcriptional Activation; United States National Institutes of Health; Variant; Viral; Viral Genome; Viral reservoir; Viremia; Virus; Virus Integration; Virus Latency; Virus Replication; activating transcription factor; antiretroviral therapy; base; biobank; biological sex; burden of illness; cohort; human DNA; integration site; mortality; promoter; receptor; viral DNA; viral RNA; viral rebound; virology; whole genome

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.

项目摘要 当前的HIV抗逆转录病毒治疗成功控制了病毒复制，并从 致命疾病，可控制慢性病。但是，尽管抑制了病毒复制 治疗，研究表明，潜在病毒储存库池仍然可检测 当抗病毒抑制治疗中断时。这些病毒储藏几乎立即建立 感染后，当HIV不可逆地将其病毒基因组整合到人DNA中时。病毒水库极为 耐用，不容易受到当前可用抗逆转录病毒药物的治疗作用，并且已经 对最近的实验治疗方法的难治性。艾滋病毒感染也以高水平的特征 病毒式准植物内基因型多样性。除了遗传多样性相关的基础替代 突变，从延长的慢性感染患者中回收的病毒DNA基因组池 抑制性疗法通常包含高频率的基因组截断和/或过度无重新杀伤的频率 合理的病毒DNA基因组。这些患者中只有一小部分病毒基因组是基因组独立 并可能在没有治疗的情况下导致生产性病毒复制和病毒学反弹。此外， 感染了由基因组独立和基因组缺陷的病毒感染的HIV感染细胞已显示为 克隆扩展，是艾滋病毒持久性的机制。但是，我们目前对艾滋病毒的理解 水库几乎完全来自对称为亚型B HIV-1的菌株的研究，占主导地位 病毒亚型影响第一世界国家，但仅占全球流行病的10％。相反，非B HIV- 1个亚型占区域，例如撒哈拉以南非洲，疾病负担在全球最高。 关于其他HIV-1子类型的剩余90％的感染的问题仍然存在问题 和构图。为了解决这个问题，我们将利用以前由NIH资助的现有生物库 乌干达艾滋病毒队列（UARTO），该队列收藏了12360个血细胞样本，纵向收集了十年 来自500个主要亚型A1和D HIV-1感染的个体。我们将使用三个尖端 技术（1）flip-seq获得接近长度的HIV-1 DNA基因组谱，（2）MIP-Seq至Copture HIV- 1个整合位点和病毒基因组，以及（3）以及完整的前病毒DNA分析（IPDA），以纵向测量 储层的衰减/膨胀率。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HIV治疗策略的靶标。跨亚型，我们将比较储层特性 包括绝对基因组独立储层大小，克隆扩张的程度，整合位点剖面，病毒 启动子基因型和纵向衰减/扩张动力学。我们将进一步调查人口统计 与基因组独立病毒相关的临床和宿主因素。总体而言，我们的目的是确定差异或缺乏 差异，HIV-1亚型水库之间的差异，以告知HIV治疗研究工作 应该是亚型特定的。