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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.

抽象的消除中枢神经系统（CNS）中的人类免疫缺陷病毒（HIV）和外周水库是治疗疾病的必要条件。据我们所知，我们是第一个实现这一目标的在有限数量的受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，最终达到根除潜伏病毒的目标。首先是新开发的神经艾滋病的人源化小鼠脑淋巴模型将有效地识别血管周围和脑膜巨噬细胞和实质细胞的有限感染。这种啮齿动物模型最接近地反映了通过强大的分子、病毒学和神经免疫学测试证明了人类大脑疾病。第二，长效缓慢有效释放抗逆转录病毒疗法（激光艺术）现已在我们的国家得到充分开发实验室现在可以对潜伏感染的病毒脑库进行精确定位。三、病毒式传播将采用切除策略来消除残留病毒并防止艾滋病毒重新激活。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 CCR5 和病毒切除策略将减少然后消除任何正在进行的感染，并整合感染者的原病毒DNA 细胞。 CRISPR/Cas9 构建体将使用特定的方法将其货物递送至大脑和周围组织位点腺相关病毒的血清型。这将能够在人源化小鼠中永久根除艾滋病毒，而无需病毒重新激活，因此可以防止任何正在进行的脑部感染和随后的神经损伤。第四，在以证明该治疗策略对脑病毒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 管理和随后的时间段（以月为单位）为病毒提供交叉验证证据通过措施反弹消灭。考虑到中枢神经系统中艾滋病毒重新激活的相关风险，这种方法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激光艺术与有效的分子病毒和免疫疗法相结合来消除病毒库。总体前提是开发永久消除所需的“最先进”工具在中枢神经系统和外周传染源中检测到病毒。