CNS Viral Escape in HIV-infected Adults

HIV 感染成人中的中枢神经系统病毒逃逸

• 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
• 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

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 本项目的目标是了解导致HIV感染成人CNS病毒逃逸的机制， 抑制性抗逆转录病毒治疗，特别是耐药性的作用。尽管目前的抗逆转录病毒药物 在抗逆转录病毒疗法（ART）中，估计4-20%的血浆抑制患者发生CSF中的病毒逃逸， 这是艾滋病治愈的障碍。与CSF逃逸相关的因素包括低水平病毒血症，既往 病毒学失败，CD 4最低点低，HIV感染持续时间长，但潜在的机制和影响 ART药物CNS渗透、耐药突变（DRM）、脑储库的大小，以及 神经炎症对脑脊液逃逸的影响尚不清楚。M184 V/I对FTC/3 TC的抗性最强， 血液中检测到的常见核苷酸逆转录酶抑制剂（NRTI）DRM。初步研究显示， M184 V/I经常在CSF逃逸患者中检测到，尽管血浆抑制， 以及CSF中的胸苷类似物耐药突变（TAM）。此外，我们还展示了一个重要的 血浆蛋白酶抑制剂（PI）为基础的ART方案与CSF逃逸之间的关系 镇压考虑到PI的CNS渗透性较低，血浆M184 V/I的患者，特别是基于PI的患者， 包括替诺福韦在内的ART由于CNS渗透不足而增加了CSF逃逸的风险 当M184 V/I存在时，ART方案的有效性降低，导致骨髓细胞库的不完全抑制， 在选择CNS中的TAM和其他DRM时，为了研究这些问题，我们将使用临床 来自充分表征的队列的样本和数据纵向跟踪，以表征 血浆、CSF和脑中正在进行的病毒复制的证据，在RT、PR和IN基因中描绘DRM， 并评估CSF逃逸患者的神经炎症和血脑屏障生物标志物。这些 研究将为CNS病毒逃逸的原因提供重要的见解，这些原因与优化临床 管理和克服艾滋病毒治愈的障碍。