Defining Factors Controlling HIV Rebound

摘要(总体) 未经治疗的艾滋病毒感染通常以病毒和宿主之间的持续战斗为特征。 免疫反应，每天产生和清除数十亿个新的病毒粒子和受感染的细胞。治疗 抗逆转录病毒疗法消除了绝大多数(或可能全部)艾滋病毒复制，血浆病毒载量经常下降到 标准临床检测无法检测到的水平。然而，某些具有复制能力的储存库 在治疗过程中，病毒会持续存在。因此，如果ART被阻止，病毒可能会从这些宿主中冒出来， 迅速传播，导致艾滋病的新进展。这个项目的目标是获得一个 更好地了解导致病毒反弹的因素，并开发新的方法来控制或 最大限度地减少停止治疗后病毒反弹。我们打算通过利用切割来解决这个问题 EDGE人源化小鼠模型，加上独特的病毒试剂，包括条形码HIV蜂群 作为额外的新试剂(嵌合抗原受体)和疫苗策略。这项计划将涉及 三个科学项目、一个行政核心(核心A)和两个科学核心。项目包括1)“定义 病毒反弹的原因和后果》，它将研究哪些因素影响细胞的激活 引起病毒反弹；2)工程免疫细胞对艾滋病毒反弹的影响，这将决定 基因工程天然细胞和记忆细胞对病毒反弹的影响；3)疫苗对形成和 清除艾滋病毒潜伏宿主“，这将决定接种疫苗的效果，接种非艾滋病毒- 特定的或特定于艾滋病毒的疫苗对病毒库和反弹。这两个科学核心将是病毒 遗传学核心(核心B)，将为所有人执行条形码病毒的测序和生物信息学分析 项目，以及人性化的鼠标核心(核心C)，它将执行所有项目的活体操作。 我们希望共同确定导致病毒反弹的因素，并可能确定辅助治疗方法 为患者提供持续的病毒学缓解的方法。

ABSTRACT (Overall) Untreated HIV infection is generally characterized by a continuous battle between the virus and the host immune response, with billions of new virions and infected cells produced and cleared every day. Treatment with ART eliminates the vast majority of (or potentially all) HIV replication, and plasma viral loads often fall to levels that are undetectable with standard clinical assays. However, certain reservoirs of replication-competent virus persist during therapy. Therefore if ART is stopped then virus can emerge from these reservoirs and rapidly spread, causing renewed progression towards AIDS. The goal of this program project is to gain a better understanding of the factors that cause this viral rebound, and to develop new methods to control or minimize viral rebound following cessation of therapy. We intend to approach this problem by utilizing cutting edge humanized mouse models, coupled with unique viral reagents, including a barcoded HIV swarm, as well as additional novel reagents (chimeric antigen receptors) and vaccine strategies. This program will involve three scientific projects, an administrative core (Core A), and two scientific cores. Projects include 1) “Defining the causes and consequences of viral rebound”, which will study what factors influence activation of cells to give rise to viral rebound; 2) “Impact of engineered immune cells on HIV rebound”, which will determine the effect of engineered innate and anamnestic cells on viral rebound; 3) “Effects of vaccines on formation and clearance of the HIV latent reservoir”, which will determine the effect of vaccination, with either a non-HIV- specific or an HIV-specific vaccine on viral reservoirs and rebound. The two scientific cores will be the Viral Genetics Core (Core B) that will perform sequencing and bioinformatics analysis of barcoded virus for all projects, and the Humanized Mouse Core (Core C), which will perform in vivo manipulations for all projects. Together we hope to define factors contributing to viral rebound, and possibly identify adjunctive therapeutic approaches to provide patients with sustained virologic remissions.