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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：
9108374
负责人：
Huanbin Xu
金额：
$ 80.94万
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/9108374
关键词：
Acquired Immunodeficiency Syndrome Animals Antibodies Antibody Response Antibody-drug conjugates Binding CD4 Positive T Lymphocytes Cancer Patient Cells Clinical Complex Detection Dose Goals HIV HIV Antibodies HIV Infections HIV-1 Health Helper-Inducer T-Lymphocyte Highly Active Antiretroviral Therapy Histone Deacetylase Inhibitor Immune Immune response Immunoglobulin M Individual Infection Inflammation Interruption Knowledge Lymphoid Tissue Macaca Macaca mulatta Modeling Morbidity - disease rate Patients Pharmaceutical Preparations Phenotype Proviruses Research Design 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 Diseases Virus Replication animal tissue antiretroviral therapy base cellular targeting design efficacy testing immune function improved functioning killings lymph nodes mTOR Inhibitor migration mortality novel novel strategies patient subsets pinacolyl methylphosphonic acid prevent prostratin purge response restoration simian human immunodeficiency virus small molecule targeted treatment treatment strategy

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.