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

• 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
• 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

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感染细胞库是治疗的关键障碍。 治愈一个被感染的人清除病毒库和预防或控制病毒反弹的策略包括 方法来驱动这些细胞进入激活状态，导致病毒复制，从而使它们 易受药物和免疫反应的影响，这些反应通过中断复制机制和识别 病毒蛋白。很可能，通过激活静息细胞免疫反应或产生新的细胞免疫反应， 接种疫苗对于在产生的生产性感染细胞释放足够的病毒体之前清除它们将是重要的 重新播种潜在的水库。产生这种免疫力的疫苗是这一总体“踢和踢”的关键策略。 杀”的方法。 然而，除了驱动抗HIV-1免疫外，疫苗还引起辅助性T细胞的免疫激活 淋巴细胞，因此可能产生HIV-1感染的新靶点，以增加潜伏库，和/或 激活已经潜伏感染的细胞，使其对HIV-1复制具有生产力。本课题 调查这些组成机制的具体目标： 目的1：评价疫苗接种对激活CD 4 + T淋巴细胞中HIV-1潜伏库的作用。 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探索 CD 4 + T细胞应答，随后是小鼠的HIV-1感染和治疗以产生潜伏的储库， 再用同样的疫苗激发休眠记忆细胞。 目的2：评估疫苗接种产生CD 8 + T淋巴细胞应答以清除免疫缺陷病毒的能力。 重新激活了HIV-1潜伏库这将使用一种新的蛋白质纳米颗粒HIV-1疫苗进行探索， 驱动高水平的CD 4+和CD 8+细胞免疫。