CNS Viral Escape in HIV-infected Adults

HIV 感染成人中的中枢神经系统病毒逃逸

基本信息

批准号：
10012218
负责人：
Dana H. Gabuzda
金额：
$ 58.27万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-23 至 2022-09-22
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10012218
关键词：
Address Adult Autopsy Bioinformatics Biological Assay Biological Markers Blood Blood - brain barrier anatomy Boston Brain Cells Cessation of life Clinical Clinical Management Cohort Analysis Cohort Studies Computer Simulation DNA Data Drug resistance Evolution Failure Genes Genotype Goals HIV HIV Infections High Prevalence Hospitals Immune In Situ Hybridization Integrase Integrase Inhibitors Lamivudine Longitudinal cohort Lymphoid Tissue Machine Learning Mediating Modeling Mutation Myeloid Cell Activation Myeloid Cell Suppression Myeloid Cells National NeuroAids Tissue Consortium Nucleotides Patients Penetration Peptide Hydrolases Pharmaceutical Preparations Phylogenetic Analysis Plasma Protease Inhibitor RNA RNA-Directed DNA Polymerase Regimen Resistance Reverse Transcriptase Inhibitors Risk Role Sampling Signal Transduction T-Lymphocyte Tenofovir Testing Thymidine Time Tissue Sample Tissues Viral Viral Load result Viral reservoir Viremia Virus Replication analog antiretroviral therapy base brain size brain tissue cohort deep sequencing insight macrophage neuroinflammation neurotropic predictive modeling pressure resistance mutation viral fitness virology white matter

Address Adult Autopsy Bioinformatics Biological Assay Biological Markers Blood Blood - brain barrier anatomy Boston Brain Cells Cessation of life Clinical Clinical Management Cohort Analysis Cohort Studies Computer Simulation DNA Data Drug resistance Evolution Failure Genes Genotype Goals HIV HIV Infections High Prevalence Hospitals Immune In Situ Hybridization Integrase Integrase Inhibitors Lamivudine Longitudinal cohort Lymphoid Tissue Machine Learning Mediating Modeling Mutation Myeloid Cell Activation Myeloid Cell Suppression Myeloid Cells National NeuroAids Tissue Consortium Nucleotides Patients Penetration Peptide Hydrolases Pharmaceutical Preparations Phylogenetic Analysis Plasma Protease Inhibitor RNA RNA-Directed DNA Polymerase Regimen Resistance Reverse Transcriptase Inhibitors Risk Role Sampling Signal Transduction T-Lymphocyte Tenofovir Testing Thymidine Time Tissue Sample Tissues Viral Viral Load result Viral reservoir Viremia Virus Replication analog antiretroviral therapy base brain size brain tissue cohort deep sequencing insight macrophage neuroinflammation neurotropic predictive modeling pressure resistance mutation viral fitness virology white matter

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项目摘要

Project Summary The goal of this project is to understand mechanisms leading to CNS viral escape in HIV-infected adults on suppressive antiretroviral therapy, particularly the role of drug resistance. Despite current antiretroviral therapies (ART), viral escape in CSF is estimated to occur in 4-20% of patients with plasma suppression, representing a barrier to HIV cure. Factors associated with CSF escape include low-level viremia, prior virologic failure, low CD4 nadir, and long duration of HIV infection, but underlying mechanisms and influence of ART drug CNS penetration, drug resistance mutations (DRMs), size of the brain reservoir, and neuroinflammation on CSF escape remain unclear. M184V/I, which confers resistance to FTC/3TC, is the most common nucleotide reverse transcriptase inhibitor (NRTI) DRM detected in blood. Preliminary studies showed M184V/I was frequently detected in patients with CSF escape despite plasma suppression, often detected together with thymidine analog resistance mutations (TAMs) in CSF. Moreover, we demonstrated a significant association between protease inhibitor (PI)-based ART regimens and CSF escape in patients with plasma suppression. Given low CNS penetration of PIs, patients with plasma M184V/I, particularly those on PI-based ART including tenofovir, have increased risk of CSF escape as a consequence of inadequate CNS penetration of ART regimens when M184V/I is present, leading to incomplete suppression of myeloid cell reservoirs in brain while selecting for TAMs and other DRMs in the CNS. To investigate these questions, we will use clinical samples and data from well-characterized cohorts followed longitudinally to characterize viral reservoirs in plasma, CSF, and brain for evidence of ongoing viral replication, profile DRMs in the RT, PR, and IN genes, and evaluate neuroinflammatory and blood-brain barrier biomarkers in patients with CSF escape. These studies will provide important insights into causes of CNS viral escape that are relevant for optimizing clinical management and overcoming obstacles to HIV cure.

项目摘要该项目的目的是了解导致艾滋病毒感染的成年人中枢神经系统病毒逃生的机制抑制性抗逆转录病毒疗法，尤其是耐药性的作用。尽管当前的抗逆转录病毒疗法（ART），CSF中的病毒逃生估计发生在4-20％的血浆抑制患者中，代表艾滋病毒治愈的障碍。与CSF逃脱相关的因素包括低级病毒血症病毒学衰竭，低CD4 Nadir和HIV感染的持续时间，但基本机制和影响 ART药物CNS渗透，耐药性突变（DRM），大脑储层的大小和 CSF逃生的神经炎症尚不清楚。 M184V/i，对FTC/3TC的抵抗力是最多的在血液中检测到的常见核苷酸逆转录酶抑制剂（NRTI）DRM。初步研究表明尽管血浆抑制了CSF的患者，经常检测到M184V/I，经常被检测到与CSF中的胸苷类似物抗性突变（TAM）一起。此外，我们证明了一个重要的血浆患者的蛋白酶抑制剂（PI）基于ART方案和CSF逃生之间的关联抑制。鉴于PI的CNS渗透率低，血浆M184V/I的患者，尤其是基于PI的患者包括Tenofovir在内的艺术，由于CNS穿透不足而增加了CSF逃脱的风险 M184V/I存在的艺术方案，导致不完全抑制髓样细胞库大脑在中枢神经系统中选择TAM和其他DRM。为了调查这些问题，我们将使用临床来自特征良好的队列的样本和数据纵向遵循，以表征病毒储存库血浆，CSF和大脑，用于持续的病毒复制的证据，RT，PR和基因中的DRM，并评估CSF逃生患者的神经炎症和血脑屏障生物标志物。这些研究将为CNS病毒逃生的原因提供重要的见解，这与优化临床有关管理和克服艾滋病毒治愈的障碍。