High-Definition Characterization of the Persistence and Perturbation of the HIV Reservoir: Project 2

HIV 病毒库的持续性和扰动的高清表征：项目 2

基本信息

批准号：
10654776
负责人：
Mathias Lichterfeld
金额：
$ 46.5万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10654776
关键词：
Acute Address Anatomy Anti-Retroviral Agents Astrocytes Autopsy Biological Assay Blood Blood Vessels Blood specimen Brain region CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cells Central Nervous System Central Nervous System Agents Central Nervous System Infections Cerebrospinal Fluid Cessation of life Clinical Clonality Cloning Collaborations Collection Colon Combined Modality Therapy Competence Computer Models Critical Pathways Data Analytics Development Drug resistance Event Evolution Frequencies Functional disorder Future Genes Genetic Genome Genomics Goals HIV HIV Infections HIV-1 Human Human body Immune Immune system Immunohistochemistry Immunologics In Situ Hybridization In Vitro Individual Infection Interdisciplinary Study Interruption Length Location Longitudinal Studies Lymphoid Tissue Macrophage Maintenance Maps Measures Mediating Microglia Minor Modeling Myelogenous Neurocognitive Neurology Pathogenesis Pathway interactions Patients Phylogenetic Analysis Plasma Population Predisposition Primary Infection Procedures Proviruses Research Personnel Research Project Grants Resolution Role Sampling Sorting Spleen T-Lymphocyte Epitopes Technology Therapeutic Intervention Time Tissues Viral Viral reservoir Viremia Virus Diseases Virus Replication body system brain cell chromosomal location clinical care comparative data modeling experience fitness ileum insight integration site lymph nodes migration neuropathology neutralizing antibody next generation sequencing novel peripheral blood prevent repository single molecule technology development therapeutic development tool urogenital tract vector viral rebound virology

项目摘要

Abstract A considerable number of clinical, neuropathological, immunohistochemical and immunological studies suggest that human brain cells, in particular those of myeloid origin, are susceptible to HIV-1; infection of these cells may contribute to neurocognitive dysfunction and viral long-term persistence despite ART. However, among all anatomical tissue locations in the human body, the central nervous system (CNS) arguably represents the most difficult one to access and to evaluate for viral infection and persistence. Recently, significant progress has been made in defining viral reservoirs using novel next-generation sequencing approaches, frequently allowing viral sequence profiling at single-genome or single-cell resolution. Using such technologies, it is possible to profile the evolutionary dynamics of viral species in the CNS in great detail, and to obtain rare insight into the underlying mechanisms and pathways that influence HIV-1 reservoir establishment and persistence in the CNS. Here, we propose a collaborative, interdisciplinary research project involving investigators with complementary experience in neurology, neuropathology, virology, computational modeling and clinical care of HIV-1 patients to advance the current understanding of the CNS as an anatomical site for long-term persistence of replication-competent HIV-1. In specific aim 1, we will leverage a unique collection of paired CSF and plasma samples from longitudinally-followed, untreated HIV-1 patients to evaluate phylogenetic associations and interrelated viral population genomics between viral sequences from the CNS and alternative anatomical compartments; these studies will be instrumental for tracking the seeding and establishment of long-lasting viral reservoirs pre-ART. In specific aim 2, we will use autopsy material from ART-treated HIV-1 patients with suppressed viremia at death to profile the frequency, clonality, chromosomal location and replication competence of proviruses isolated from sorted CNS cells, in particular from myeloid parenchymal microglia, from myeloid perivascular macrophages and astrocytes. Together, these studies will allow for a deep characterization of HIV-1 reservoir cell dynamics in the CNS, and may be informative for future clinical strategies aiming at HIV-1 eradication and cure.

抽象的大量临床、神经病理学、免疫组织化学和免疫学研究表明人类脑细胞，特别是骨髓来源的脑细胞，容易感染 HIV-1；这些细胞的感染可能尽管接受了抗逆转录病毒治疗，病毒仍会导致神经认知功能障碍和病毒长期持续存在。然而，在所有从人体的解剖组织位置来看，中枢神经系统（CNS）可以说是最重要的。难以获取和评估病毒感染和持久性。近期，取得了重大进展使用新颖的下一代测序方法定义病毒库，通常允许病毒单基因组或单细胞分辨率的序列分析。使用此类技术，可以分析详细了解中枢神经系统中病毒物种的进化动态，并获得对潜在机制的罕见洞察影响 HIV-1 储存库在中枢神经系统中建立和持续存在的机制和途径。在这里，我们提出一个合作的、跨学科的研究项目，涉及具有互补经验的研究人员在神经学、神经病理学、病毒学、计算模型和 HIV-1 患者的临床护理方面取得进展目前对中枢神经系统作为具有复制能力的长期存在的解剖部位的理解 HIV-1。在具体目标 1 中，我们将利用来自以下组织的独特的配对脑脊液和血浆样本集合：纵向跟踪、未经治疗的 HIV-1 患者，以评估系统发育关联和相互关联的病毒来自中枢神经系统和替代解剖区室的病毒序列之间的群体基因组学；这些研究将有助于跟踪 ART 前的长期病毒库的播种和建立。在具体目标 2 中，我们将使用接受 ART 治疗且死亡时病毒血症受到抑制的 HIV-1 患者的尸检材料分析从以下来源分离的原病毒的频率、克隆性、染色体位置和复制能力分选的中枢神经系统细胞，特别是来自骨髓实质小胶质细胞、来自骨髓血管周围巨噬细胞和星形胶质细胞。总之，这些研究将有助于深入表征 HIV-1 储存细胞动力学 CNS，并且可能为未来旨在根除和治愈 HIV-1 的临床策略提供信息。