Targeting_the_Source_of_Persistent_HIV_Viremia

持续性 HIV 病毒血症的目标来源

• 批准号: 8047422
• 负责人: Sarah Elizabeth Palmer
• 金额: $ 25.03万
• 依托单位: KAROLINSKA INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-15 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8047422
• 关键词: AIDS/HIV problem; Academic Medical Centers; Address; Aftercare; Animal Model; Animals; Anti-HIV Agents; Anti-Retroviral Agents; Antiviral Agents; Biological Assay; Blood Cells; Bone Marrow; CD4 Positive T Lymphocytes; California; Cell Lineage; Cells; Cerebrospinal Fluid; Clinical Research; Clinical Treatment; Clinical Trials; Communicable Diseases; DNA Methylation; DNA Sequence; Disease Management; Europe; Funding; Future; Gene Activation; General Hospitals; Genetic; Genetic Transcription; Genome; Goals; Gut associated lymphoid tissue; HIV; HIV Infections; HIV therapy; HIV-1; Histone Deacetylation; Human; Immune; In Vitro; Infection; Institutes; Institution; Knowledge; Label; Life; Ligation; Lymph Node Tissue; Macaca; Measures; Mediating; Medical Research; Memory; Methods; Methylation; Modeling; Molecular; Molecular Genetics; Netherlands; Neuraxis; Neurology; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacotherapy; Phylogenetic Analysis; Plasma; Plasma Cells; Population; Population Genetics; Principal Investigator; Production; Publishing Peer Reviews; RNA; RNA Sequences; Regimen; Reporting; Research; Research Personnel; Residual state; San Francisco; Signal Transduction; Site; Source; Surface; T memory cell; Techniques; Testing; Therapeutic; Tissues; Translational Research; Treatment Protocols; United States; Universities; Viral; Viremia; Virion; Virus; Work; antiretroviral therapy; base; cell type; disorder control; drug development; drug testing; effective therapy; efficacy testing; genome sequencing; in vivo; inhibitor/antagonist; killings; memory CD4 T lymphocyte; particle; peripheral blood; prevent; programs; success; tool; transcription factor; viral DNA; viral RNA

Current antiretroviral therapy is not curative and does not eradicate HIV-1 viremia. Rather, the virus persists and is merely suppressed during therapy. The source and dynamics of this persistent viremia is currently unknown. Determining the source of persistent viremia during combination antiretroviral therapy will inform future efforts aimed at viral eradication. To address these important issues the current study puts forward two hypotheses. First, to identify the source of persistent viremia in patients on suppressive therapy we must compare HIV populations in patient plasma to the HIV populations found in the cerebrospinal fluid (CSF), cells from peripheral blood and cells isolated from other tissues. Second, activating the latently HIV-infected cell will induce the expression of the integrated HIV genome making it vulnerable to immune-mediated killing and therapy. To test these hypotheses we seek to achieve three specific aims. First, we will characterize the HIV-1 genetic populations in plasma, CSF and a broad spectrum of HIV-infected cells from peripheral blood, gut associated lymphoid tissue (GALT), lymph node tissue (LNT), and bone marrow tissue (BMT) from patients on suppressive therapy using such methods as single-genome sequencing and single-proviral sequencing. The phylogenetic relatedness of the plasma-derived viral RNA sequences and intracellular viral DNA sequences will be determined. The comparison of HIV populations from plasma to different cellular and tissue compartments will allow us to investigate and seek to identify the source and genetic dynamics of persistent viremia in patients on suppressive therapy. For our second aim, we will apply peer-reviewed and published ligation-based molecular tools known as proximity ligation probes to specifically label and measure HIV virions and identify the cellular source of these particles. This will be important for identifying the cell lineage producing virions during suppressive therapy. Third, we will use new inhibitors of DNA methylation, protein methylation or histone deacetylation to stimulate cellular HIV transcription and therefore release of HIV from latently infected memory CD4+ T-cells, making the virus vulnerable to antiretroviral drugs. To accomplish this aim, we will culture CD4+ memory T-cells from patients on suppressive therapy and expose these cells to the new inhibitors. This research plan will bring together a diverse, multinational group of experts from Europe and United States specializing in HIV translational research, HIV clinical treatment, molecular genetics, and antiviral drug development.

目前的抗逆转录病毒疗法无法治愈，也不能根除 HIV-1 病毒血症。相反，病毒仍然存在 并且仅在治疗期间被抑制。这种持续性病毒血症的来源和动态目前是 未知。确定联合抗逆转录病毒治疗期间持续病毒血症的来源将有助于 未来的努力旨在根除病毒。为了解决这些重要问题，当前的研究提出了两个 假设。首先，为了确定接受抑制治疗的患者持续性病毒血症的根源，我们必须 将患者血浆中的 HIV 群体与脑脊液 (CSF)、细胞中发现的 HIV 群体进行比较 来自外周血和从其他组织分离的细胞。其次，激活潜伏感染艾滋病毒的细胞 诱导整合的 HIV 基因组的表达，使其容易受到免疫介导的杀伤， 治疗。为了检验这些假设，我们寻求实现三个具体目标。首先，我们将描述 HIV-1 的特征 血浆、脑脊液和外周血、肠道中广泛的 HIV 感染细胞中的遗传群体 来自患者的相关淋巴组织（GALT）、淋巴结组织（LNT）和骨髓组织（BMT） 使用单基因组测序和单病毒测序等方法进行抑制治疗。这 血浆来源的病毒RNA序列和细胞内病毒DNA序列的系统发育相关性 将被确定。血浆与不同细胞和组织中 HIV 群体的比较 区室将使我们能够调查并寻求确定持久性的来源和遗传动态 接受抑制治疗的患者出现病毒血症。对于我们的第二个目标，我们将应用同行评审和发布 基于连接的分子工具，称为邻近连接探针，用于特异性标记和测量 HIV 病毒体 并确定这些颗粒的细胞来源。这对于识别细胞谱系很重要 在抑制治疗期间产生病毒粒子。第三，我们将使用新的DNA甲基化抑制剂、蛋白质 甲基化或组蛋白去乙酰化可刺激细胞 HIV 转录，从而释放 HIV 潜伏感染的记忆 CD4+ T 细胞，使病毒容易受到抗逆转录病毒药物的影响。为了实现这一点 我们的目标是培养来自接受抑制治疗的患者的 CD4+ 记忆 T 细胞，并将这些细胞暴露于 新的抑制剂。该研究计划将汇集来自欧洲和欧洲的多元化跨国专家组。 美国专门从事艾滋病毒转化研究、艾滋病毒临床治疗、分子遗传学和 抗病毒药物开发。