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.

潜伏感染HIV-1的细胞在抗逆转录病毒治疗期间持续存在是一个关键障碍 治愈感染者。清除病毒蓄水池并防止或控制病毒反弹的策略包括 驱动这些细胞进入激活状态从而导致病毒复制的方法，从而使它们 对药物和免疫反应敏感，这些反应通过中断复制机制和识别 病毒蛋白。驱动静止的细胞免疫反应或创造新的细胞免疫反应 接种疫苗对于在产生大量感染细胞释放足够的病毒粒子之前清除它们是很重要的。 为潜在的储集层补种。产生这种免疫力的疫苗是这一总体“踢和”的关键战略 “杀戮”的方法。 然而，除了促进抗HIV-1免疫外，疫苗还导致辅助T细胞的免疫激活 淋巴细胞，因此可能为HIV-1感染创造新的靶点，以增加潜在的储备库，和/或 激活已经潜伏感染的细胞，使其成为HIV-1复制的生产性细胞。在这个项目中，我们 以特定目标调查这些组件机制： 目的1：评价疫苗对重新激活HIV-1潜伏库的作用。 将在人源化小鼠中使用非HIV-1疫苗来探索这一点，以产生预先存在的静止记忆 CD4+T细胞反应，随后感染HIV-1的小鼠和治疗产生潜伏的蓄水池， 并用同样的疫苗再次挑战，以驱动静止的记忆细胞的激活。 目的2：评价疫苗产生CD8+T淋巴细胞反应的能力 重新激活HIV-1潜伏蓄水池。将使用一种新的蛋白质纳米粒子HIV-1疫苗来探索这一点 促进高水平的CD4+和CD8+细胞免疫。