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：
10226142
负责人：
OTTO O YANG
金额：
$ 33.68万
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 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10226142
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伏 HIV-1 感染细胞库是抗逆转录病毒治疗的关键障碍治愈感染者并预防或控制病毒反弹的策略包括驱动这些细胞进入激活状态的方法，从而导致病毒复制，使它们容易受到药物和免疫反应的影响，这些反应通过中断复制机制并识别病毒蛋白可能分别通过驱动静息细胞免疫反应或产生新的免疫反应。疫苗接种对于在释放足够的病毒粒子之前清除产生的有效感染细胞非常重要重新接种疫苗以产生这种免疫力是这一整体“踢与踢”的关键策略。杀”的做法。然而，除了驱动抗 HIV-1 免疫力之外，疫苗还会引起辅助性 T 细胞的免疫激活淋巴细胞，因此有可能为 HIV-1 感染创造新的目标，以添加到潜在的储存库中，和/或激活已经潜伏感染的细胞，使其能够进行 HIV-1 复制。研究具有特定目标的这些组成机制：目标 1：评估疫苗接种对重新激活 CD4+ T 淋巴细胞中 HIV-1 潜伏病毒库的影响。这将通过在人源化小鼠中使用非 HIV-1 疫苗来产生预先存在的静息记忆来进行探索 CD4+ T 细胞反应，然后是小鼠的 HIV-1 感染和治疗以产生潜在的储存库，并用相同的疫苗重新激发，以驱动静息记忆细胞的激活。目标 2：评估疫苗接种产生 CD8+ T 淋巴细胞反应以清除重新激活的 HIV-1 潜伏病毒库将使用一种新型蛋白质纳米颗粒 HIV-1 疫苗进行探索。驱动高水平的 CD4+ 和 CD8+ 细胞免疫。