Persistent Virus Reservoirs in SIV-infected Macaques

感染 SIV 的猕猴体内的持久病毒库

基本信息

批准号：
8598455
负责人：
Mirko Paiardini
金额：
$ 22.12万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-01 至 2015-05-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8598455
关键词：
Acquired Immunodeficiency Syndrome Address Adherence Anatomy Animals Anti-Retroviral Agents Applications Grants Biological Assay Biology CD4 Positive T Lymphocytes Cells DNA Sequence Data Disease Drug toxicity Evolution HIV HIV Infections Highly Active Antiretroviral Therapy Histone Deacetylase Inhibitor Histones Human Immune Individual Infection Inflammation Intervention Knowledge Latent virus infection phase Life Location Longevity Lymphoid Tissue Macaca Macaca mulatta Maintenance Measures Memory Modeling Morbidity - disease rate Mucous Membrane Nature Organ Pathway interactions Patients Persons Pharmaceutical Preparations Phase Phylogenetic Analysis Plasma Process Public Health Regimen Research Residual state Resources Reverse Transcriptase Polymerase Chain Reaction Risk SIV Source Staining method Stains System T-Lymphocyte Subsets Testing Therapeutic Tissue Sample Tissues Viral Viral Load result Virus Virus Diseases Virus Replication Vorinostat antiretroviral therapy base immune activation in vivo inhibitor/antagonist insight mortality nonhuman primate novel novel strategies novel therapeutics peer peripheral blood public health relevance reconstitution research study viral DNA

项目摘要

DESCRIPTION (provided by applicant): Despite many advances in AIDS research, including the availability of potent anti-retroviral therapy (ART) that effectively controls virus replicatio in a large proportion of HIV-infected patients, a treatment that can cure the infection remains elusive. To this end, new approaches are required to eradicate the reservoirs of latently infected cells that persist during ART and are the source of virus reactivation when therapy is interrupted. In the R21 phase of this grant application we propose to use the existing, well-established non-human primate model of SIVmac infection of rhesus macaques (RMs) to validate studies of HIV eradication/functional cure by developing an experimental system in which virus replication is fully and persistently suppressed in vivo by a potent ART regimen (Aim 1). We will then use this validated model to investigate directly in vivo and in multiple organs th anatomic and phenotypical nature of the persistent reservoirs of latently infected cells, with specific focus on the relationship between expression of co-inhibitory molecules (i.e. PD-1, CTLA-4, TIM-3, and LAG-3) and size of the persistent reservoirs (Aim 2). The results of the studies proposed in the R21 part of this application will pave the way for further experiments, to be conducted in the R33 phase of this proposal, in which we will test, in ART-treated SIV-infected RMs with full suppression of virus replication, immune-based interventions aimed at reducing and possibly eliminating in vivo the persisting reservoirs of latently infected cells. The key proposed intervention consists of a blockade of the co-inhibitory pathway most closely associated with SIV latency, which will be performed as a stand-alone therapy or in combination with a non-specific virus reactivating agent (i.e. the histone deacytelase inhibitor, SAHA). We believe that the proposed studies will provide unprecedented insights into the biology of persistent virus reservoirs of latently infected cells, and elucidate the potential of targeting co inhibitory pathways to reduce the reservoir during SIV infection.

描述（由申请人提供）：尽管艾滋病研究取得了许多进展，包括有效控制大部分艾滋病毒感染患者体内病毒复制的有效抗逆转录病毒疗法（ART）的出现，但治愈感染的治疗方法仍然难以捉摸。为此，需要新的方法来根除 ART 期间持续存在的潜伏感染细胞库，这些细胞是治疗中断时病毒重新激活的根源。在本次拨款申请的 R21 阶段，我们建议使用现有的、完善的恒河猴 (RM) SIVmac 感染非人类灵长类动物模型，通过开发病毒复制的实验系统来验证 HIV 根除/功能性治愈的研究。通过有效的 ART 方案在体内完全且持续地抑制（目标 1）。然后，我们将使用这个经过验证的模型直接研究体内和多个器官中潜伏感染细胞持久储存库的解剖和表型性质，特别关注共抑制分子（即 PD-1、CTLA）表达之间的关系。 -4、TIM-3 和 LAG-3）和持久性储层的大小（目标 2）。本申请的 R21 部分中提出的研究结果将为进一步的实验铺平道路，这些实验将在本提案的 R33 阶段进行，我们将在接受 ART 治疗的 SIV 感染 RM 中进行测试，并完全抑制病毒复制、基于免疫的干预措施旨在减少并可能消除体内持续存在的潜伏感染细胞。这拟议的关键干预措施包括阻断与 SIV 潜伏期最密切相关的共抑制途径，该途径将作为独立疗法或与非特异性病毒再激活剂（即组蛋白脱乙酰酶抑制剂，SAHA）联合进行。我们相信，所提出的研究将为潜伏感染细胞的持久病毒库的生物学提供前所未有的见解，并阐明靶向共存病毒的潜力。 SIV 感染期间减少储存的抑制途径。