权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Combined Molecular Excision Therapy (CMET) for Eliminating HIV-1

用于消除 HIV-1 的联合分子切除疗法 (CMET)

基本信息

批准号：
10217975
负责人：
Howard E Gendelman
金额：
$ 67.63万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-20 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10217975
关键词：
Academic Medical Centers Anti-Retroviral Agents Astrocytes Bone Marrow Brain Brain Diseases CCR5 gene CD4 Positive T Lymphocytes CRISPR/Cas technology Cells Combined Modality Therapy Communication Complex Confocal Microscopy Coupled Crystallization DNA Dependovirus Development Disease Drug Kinetics Effectiveness Evaluation Excision Flow Cytometry Formulation Foundations Gene Delivery Gene Expression Genes Genitourinary system Goals Gut associated lymphoid tissue HIV HIV Genome HIV-1 Hematopoietic stem cells Human Hydrophobicity Immune Immune system Immunohistochemistry Infection Laboratories Lamivudine Lasers Latent virus infection phase Lead Lymphoid Lymphoid Tissue Measurement Measures Mediating Membrane Meningeal Modeling Molecular Molecular Virology Mus Neoadjuvant Therapy Neuraxis Neuroglia Neuroimmune Nucleic Acids Oligodendroglia Peripheral Pharmaceutical Chemistry Pharmaceutical Preparations Polymer Chemistry Polymerase Chain Reaction Proviruses Regimen Research Activity Research Personnel Residual state Rest Risk Rodent Model Serotyping Site Spleen System Techniques Testing Therapeutic Time Tissues Transgenic Mice Translating Transplantation Treatment outcome Universities Validation Viral Viral Genes Viral Load result Viral Proteins Viral reservoir Virus Virus Latency abacavir adeno-associated viral vector antiretroviral therapy base brain tissue clinical translation crystallinity cytotoxicity expectation human disease humanized mouse immunogenicity improved in vivo indexing lipophilicity lymph nodes lymphoblast macrophage mouse model nanoparticle nanoparticle delivery nerve stem cell neuroAIDS novel receptor reconstitution relating to nervous system success tool vector viral DNA viral rebound

项目摘要

Abstract The elimination of the human immunodeficiency virus (HIV) from its central nervous system (CNS) and peripheral reservoirs is a requirement for a disease-cure. To our knowledge, we are the first to have achieved this goal in tests performed in a limited number of infected humanized mice. To validate such early successes we propose to build a four-step ladder with a final crest of latent virus eradication. First, a newly developed humanized mouse brain-lymphoid model of neuroAIDS will identify productively infected perivascular and meningeal macrophages and restricted infection in parenchymal cells. This rodent model most closely reflects human brain disease as demonstrated by robust molecular, virologic and neuroimmunologic tests. Second, long acting slow effective release antiretroviral therapy (LASER ART) also now fully developed in our laboratories can now facilitate a pinpoint localization of the latently infected viral brain reservoir. Third, viral excision strategies will be employed to eliminate residual virus and preclude HIV reactivation. The gene editing CRISPR/Cas9 system developed by Temple University Medical Center investigators including CCR5 and viral excision strategies will reduce then eliminate any ongoing infection and integrated proviral DNA from infected cells. The CRISPR/Cas9 constructs will deliver its cargo to brain and peripheral tissue sites using specific serotypes of adeno-associated virus. This will enable permanent HIV eradication in humanized mice without viral reactivation and as such preclude any ongoing brain infection and subsequent neural damage. Fourth, in order to prove the therapeutic strategy effective both for brain and peripheral lymphoid tissue virus (including the gut-associated lymphoid tissue, lymph node, spleen and genitourinary system) we will cease ART administrations and following time periods measured in months to provide cross validating evidence for viral eradication by measure rebound. Given the risks associated with HIV reactivation in the CNS this approach must show effectiveness for its abilities to target latent virus. Taken together, the proposal seeks support to employ combination LASER ART and potent molecular viral and immune-based regimens for elimination of viral depots. The overall premise is to develop the “state of the art” tools required to permanently eliminate virus detected in the CNS and peripheral infectious reservoirs.

摘要从中枢神经系统（CNS）消除人类免疫缺陷病毒（HIV），外周储库是治疗疾病的必要条件。据我们所知，我们是第一个在有限数量的感染的人源化小鼠中进行的测试中实现了这一目标。为了验证这些早期的成功，我们建议建立一个四级阶梯，最后达到消灭潜伏病毒的顶点。首先，新开发的 neuroAIDS的人源化小鼠脑淋巴模型将有效地鉴定血管周围感染，脑膜巨噬细胞和实质细胞中的限制性感染。这个啮齿动物模型最能反映通过强有力的分子、病毒学和神经免疫学测试证实的人类脑部疾病。第二、长效缓释抗逆转录病毒疗法（LASER ART）现在也在我们的国家得到了充分的发展。实验室现在可以方便地精确定位潜伏感染的病毒大脑储存库。第三，病毒性将采用切除策略来消除残留病毒并防止HIV再活化。基因编辑天普大学医学中心研究人员开发的CRISPR/Cas9系统，包括CCR 5和病毒切除策略将减少然后消除任何正在进行的感染，并将整合的前病毒DNA从感染的细胞CRISPR/Cas9构建体将使用特定的细胞因子将其货物递送到大脑和外周组织部位。腺相关病毒的血清型。这将使人源化小鼠中的HIV永久根除成为可能，病毒再激活，从而防止任何正在进行的脑感染和随后的神经损伤。四是为了证明治疗策略对脑和外周淋巴组织病毒（包括肠道相关淋巴组织、淋巴结、脾脏和泌尿生殖系统），我们将停止ART 给药和随后的时间段（以月为单位测量），以提供病毒感染的交叉验证证据。根除措施反弹。考虑到与CNS中HIV再活化相关的风险，必须显示其针对潜伏病毒的能力的有效性。总的来说，该提案寻求支持，采用联合激光ART和有效的分子病毒和免疫为基础的方案，以消除病毒库总的前提是开发永久消除在CNS和外周感染性宿主中检出病毒。