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（由申请人提供）：高效抗逆转录病毒治疗已显着降低 HIV-1 复制和病毒血症至临床检测限以下，并减缓进展为 AIDS 的速度。然而，残留病毒库仍以潜伏状态持续存在。尽管进行了长期抗逆转录病毒治疗（ART），但仍存在整合且转录沉默的原病毒，导致 HIV-1 感染者在停止 ART 后终生感染和病毒反弹治愈 HIV 感染的主要障碍是如何清除隐窝组织中持续和潜伏的 HIV 感染细胞，特别是在生发中心 (GC)。通过我们的新型调节治疗策略，我们将逆转潜伏病毒感染的细胞，阻止 GC 中新储存库的补充，同时在 GC 中引发次优势的 IgM 反应。为了实现这一目标，我们将依次给予 ART，联合 PKC 激活剂前列腺素 (PRO) 和免疫调节 mTOR 抑制剂雷帕霉素 (RAPA)，然后使用抗 HIV-1 包膜抗体药物偶联物 (ADC)，以消除残留感染。我们追求的这种全面的“休克和杀死”策略还将导致受感染宿主中 CTL 功能的恢复和抗体反应的改善，这两者结合起来可能会导致灭菌，或者至少会导致灭菌。这种治疗策略的可行性、安全性和有效性将在恒河猴的 HIV 感染相关 SHIV 模型中进行测试。我们的长期目标是开发一种针对 HIV 感染的绝育疗法。患者，这些研究将为这一雄心勃勃的目标的可行性和实用性提供关键信息。