Effects of Vaccine on Formation and Clearance of the HIV Latent Reservoir

疫苗对 HIV 潜伏病毒库形成和清除的影响

基本信息

批准号：
10057935
负责人：
OTTO O YANG
金额：
$ 33.84万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-10 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10057935
关键词：
Amino Acid Sequence Antiviral Agents Area Automobile Driving CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cells Cellular Immunity Complement Containment Cytolysis Disease Disease Progression Drops Evolution Generations Genetic Determinism Genetic Transcription Genome Scan HIV HIV-1 HIV-1 vaccine Helper-Inducer T-Lymphocyte Humoral Immunities Immune response Immunity Immunologic Memory In Vitro Infection Influenza vaccination Interruption Macaca Maintenance Major Histocompatibility Complex Memory Modeling Mus Pathogenesis Persons Pharmaceutical Preparations Production Program Research Project Grants Proteins Proviruses Research Rest Reverse Transcription SIV T cell response T-Lymphocyte Vaccination Vaccines Variant Viral Proteins Viremia Virion Virus Diseases Virus Replication acute infection adaptive immunity antiretroviral therapy arm cytokine driving force humanized mouse immune activation immune clearance in vivo interest latent HIV reservoir memory CD4 T lymphocyte nanoparticle novel prevent purge response targeted treatment transcription factor viral rebound

项目摘要

The reservoir of latently HIV-1-infected cells that persist during antiretroviral therapy is a critical barrier to curing an infected person. Strategies to purge this reservoir and prevent or control viral rebound include approaches to drive these cells into an activated state that causes viral replication, thereby rendering them susceptible to drugs and immune responses, which act by interrupting replication mechanisms and recognizing viral proteins respectively. It is likely that driving resting cellular immune responses or creating new ones via vaccination will be important to clear the resulting productively infected cells before they release enough virions to reseed the latent reservoir. Vaccines to generate such immunity are a key strategy in this overall “kick and kill” approach. In addition to driving anti-HIV-1 immunity, however, vaccines also cause immune activation of helper T lymphocytes, therefore potentially creating new targets for HIV-1 infection to add to the latent reservoir, and/or activating already latently-infected cells to become productive for HIV-1 replication. In this project, we investigate these component mechanisms with the specific aims: Aim 1: To evaluate the effect of vaccinations on reactivating the HIV-1 latent reservoir in CD4+ T lymphocytes. This will be explored using non-HIV-1 vaccines in humanized mice to generate pre-existing resting memory CD4+ T cell responses, followed by HIV-1 infection of the mice and treatment to generate a latent reservoir, and re-challenge with the same vaccines to drive activation of the resting memory cells. Aim 2: To evaluate the capacity of vaccinations to generate CD8+ T lymphocyte responses for clearing the reactivated HIV-1 latent reservoir. This will be explored using a novel protein nanoparticle HIV-1 vaccine that drives both CD4+ and CD8+ cellular immunity at high levels.

在抗逆转录病毒治疗期间持续存在的潜在HIV-1感染细胞的储层是对治愈感染者。清除该水库和预防或控制病毒反弹的策略包括将这些细胞驱动到引起病毒复制的激活状态的方法，从而使它们呈现容易受到药物和免疫调查的影响，这些药物通过中断复制机制并认识到病毒蛋白分别。驱动静息蜂窝免疫反应或通过疫苗接种对于清除产生的有效感染的细胞在释放足够的病毒之前将很重要恢复潜在水库。产生这种免疫力的疫苗是这一总体“踢和杀人”方法。但是，除了驱动抗HIV-1免疫组织化学外，疫苗还引起辅助辅助剂T 因此，淋巴细胞有可能为HIV-1感染创造新的靶标，以添加到潜在储层和/或激活已经受感染的细胞，以生产HIV-1复制。在这个项目中，我们以具体目的研究这些组件机制：目标1：评估疫苗接种对CD4+ T淋巴细胞中HIV-1潜在储层的影响。这将在人源化小鼠中使用非HIV-1疫苗进行探讨，以生成预先存在的静止记忆 CD4+ T细胞反应，然后是小鼠的HIV-1感染，并产生潜在储层，并用相同的疫苗重新挑战以驱动静息记忆细胞的激活。目的2：评估疫苗接种产生CD8+ T淋巴细胞反应的能力以清除重新激活HIV-1潜在储层。将使用一种新型蛋白质纳米颗粒HIV-1疫苗来探讨这一点在高水平的情况下驱动CD4+和CD8+细胞免疫。