Novel strategies for eliminating HIV reservoirs in lymphoid tissues

消除淋巴组织中艾滋病毒储存库的新策略

基本信息

批准号：
9306087
负责人：
Huanbin Xu
金额：
$ 80.44万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-10 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9306087
关键词：
Acquired Immunodeficiency Syndrome Animals Antibodies Antibody Response Antibody-drug conjugates Binding CD4 Positive T Lymphocytes Cancer Patient Cells Clinical Combined Modality Therapy Complex Detection Dose Genetic Transcription Goals HIV HIV Antibodies HIV Infections HIV-1 Helper-Inducer T-Lymphocyte Highly Active Antiretroviral Therapy Histone Deacetylase Inhibitor Immune Immune response Immunoglobulin M Individual Infection Inflammation Interruption Knowledge Latent Virus Lymphoid Tissue Macaca Macaca mulatta Modeling Morbidity - disease rate Pathogenicity Patients Pharmaceutical Preparations Phenotype Proviruses Residual state Safety Series Shock Sirolimus Site Structure of germinal center of lymph node T-Lymphocyte Testing Therapeutic Therapeutic Studies Tissues Viral Viral reservoir Viremia Virus Virus Latency Virus Replication animal tissue antiretroviral therapy base cell motility cellular targeting design efficacy testing immune function immunoregulation improved killings lymph nodes mTOR Inhibitor migration mortality novel novel strategies patient subsets pinacolyl methylphosphonic acid prevent prostratin public health relevance purge response restoration simian human immunodeficiency virus small molecule targeted treatment treatment strategy viral rebound

项目摘要

DESCRIPTION (provided by applicant): Highly active antiretroviral therapy has dramatically reduced HIV-1 replication and viremia below the clinical limit of detection, and slows the rate of progression to AIDS. However, residual viral reservoirs still persist in a latent state in the formof integrated and transcriptionally silent proviruses, despite long-term antiretroviral therapy (ART), resulting in lifelong infection and viral rebounds in HIV-1-infected individuals upon ART cessation. The major obstacle to a cure for HIV infection is how to purge the persistently and latently HIV- infected cells in recessed tissues, especially in germinal centers (GC) of organized lymphoid tissues. With our novel-modulatory therapeutic strategy, we will reverse latently virus-infected cells, block replenishment of new reservoirs in GC, while simultaneously eliciting subdominant IgM responses in macaques on suppressive ART. To accomplish this we will sequentially administer ART, combined with the PKC activator prostratin (PRO) and immunomodulatory mTOR inhibitor rapamycin (RAPA) followed by anti-HIV-1 envelope antibody-drug conjugates (ADC) to eliminate residual infected cells. We hypothesize this comprehensive "shock and kill" strategy will also result in restoration of CTL function and improved antibody responses in infected hosts, which combined, may result in a sterilizing, or at least a "functional" cure for HIV in patients. The feasibility, safety, and efficacy of this cure strategy will be tested in the highly relevant SHIV model of HIV infection in rhesus macaques. Our long-term goal is to develop a sterilizing cure for HIV infected patients, and these studies will provide critical information as to the feasibility and practicality of this ambitious goal.

描述（由适用提供）：高度活跃的抗逆转录病毒疗法已大大降低了HIV-1复制和病毒血症以下检测的临床极限，并减慢了对艾滋病的进展率。然而，残留的病毒储存库仍然处于潜在状态，以综合和转录的静音病毒，多斯蒂斯长期抗逆转录病毒疗法（ART），导致ART停止后HIV-1感染者的终生感染和病毒反弹。治愈艾滋病毒感染的主要障碍是如何在有组织的淋巴组织组织的凹入组织中持续清除感染的HIV感染细胞（尤其是在生发中心（GC）中）。通过我们的新型调节理论策略，我们将逆转潜在的病毒感染的细胞，阻止GC中新储层的复制，同时在抑制性艺术的猕猴中引起亚抑制IgM反应。为了实现这一目标，我们将与PKC激活剂Prostratin（Pro）和免疫调节剂MTOR MTOR抑制剂雷帕霉素（RAPA）结合使用抗HIV-HIV-1包膜抗体抗体-Drug conjugates（ADC），以消除残余感染细胞。我们假设这种全面的“冲击和杀戮”策略还将导致CTL功能的恢复，并改善感染宿主的抗体反应，这可能会导致对患者的HIV进行灭菌或至少“功能性”治疗。该治疗策略的可行性，安全性和有效性将在恒河猕猴中高度相关的HIV感染模型中进行测试。我们的长期目标是为受HIV感染的患者开发消毒治疗，这些研究将提供有关此雄心勃勃的目标的可行性和实用性的关键信息。