SOSIP-NP/mRNA combination for novel preventive and therapeutic HIV-1 vaccine regimens

摘要 拟议研究的最终目标是为结束艾滋病毒/艾滋病流行病作出贡献。一直以来 自艾滋病毒/艾滋病流行开始以来的40年里，保护性疫苗或功能性治疗 难以捉摸。2020年，估计有3760万艾滋病毒携带者。尽管高效抗逆转录病毒 目前，仍有数十万人死于艾滋病相关疾病和数百万新感染病例 不断涌现。因此，找到结束这一大流行的方法仍然是全球的优先事项。 创新艾滋病毒/艾滋病疫苗和治疗研究联盟(CIAVCR)的总体目标是 开发一种有效的联合免疫治疗方案，用于HIV-1的预防和治疗 人类灵长类(NHP)模型，它有一条直接通往临床的路径，供人类使用。有两个FOCI 在CIAVCR中提出：在焦点1中，我们的总体目标是展示 保护性疫苗的保护，以及疫苗诱导的免疫反应在选择和限制中的作用 潜伏的储集层。使用新的信使核糖核酸结构来传递免疫原的好处 将对体液和细胞反应进行评估。在焦点2中，我们的总体目标是确定 疫苗诱导的免疫反应：1)通过缩小体积或消除HIV-1来控制HIV-1感染 和/或2)延迟血浆病毒载量的反弹。焦点1中研究的保护性疫苗将是 测试以确定疫苗诱导的B和T细胞在清除HIV-1宿主方面的反应机制。 此外，新的治疗方法将与疫苗相结合，以增加对艾滋病毒-1宿主的清除。 在焦点1和焦点2中，对突破和潜在储集层环境序列的分析将向 为一种改进的保护性疫苗方案设计新的疫苗助推器，该方案也可以限制反弹 病毒。 NHP-SHIV中央研究资源(CRR)将支持重点1和重点1中的NHP研究 2.研究疫苗诱导的多功能反应和新型免疫疗法的有效性 在清除HIV-1病毒储存库方面。这些研究将使用创新的条形码刀具来确定 疫苗诱导的清除病毒库的反应，并评估疫苗的数量和质量 在治疗中断后由潜伏期反转剂(LRA)重新激活的病毒。 管理和业务支助股(MOS)将协调科学和 CIAVCR计划的管理活动，以确保FOCI和NHP-SHIV CRR发挥作用 凝聚力强。 到这笔赠款结束时，我们希望设计出一种预防和治疗相结合的方法，以 有效预防感染，消除病毒库--有效应对艾滋病毒/艾滋病的战略 大流行。

ABSTRACT The ultimate goal of the proposed studies is to contribute to ending the HIV/AIDS epidemic. It has been four decades since the start of the HIV/AIDS epidemic and a protective vaccine or functional cure has been elusive. In 2020, there was an estimated 37.6 million people living with HIV. Despite highly active anti-retroviral therapies, hundreds of thousands of people still die from AIDS-related diseases and millions of new infections continue to emerge. Thus, finding a way to end this pandemic remains a global priority. The overall goal of the Consortium for Innovative HIV/AIDS Vaccine and Cure Research (CIAVCR) is to develop an effective combined immunotherapeutic regimen for HIV-1 prevention and cure using the non- human primate (NHP) model that has a direct path to the clinic for use in humans. There are two FOCI proposed in the CIAVCR: In FOCUS 1, our overall goal is to demonstrate the correlates and mechanisms of protection for a protective vaccine, and the role of vaccine-induced immune responses in selecting and limiting the latent reservoir. The benefits of using novel mRNA constructs to deliver immunogens that can elicit both humoral and cellular responses will be evaluated. In FOCUS 2, our overall goal is to determine the role of vaccine-induced immune responses to 1) control HIV-1 infection by reducing the size or eliminating HIV-1 reservoirs, and/or 2) delay plasma virus load rebound. The protective vaccines studied in FOCUS 1 will be tested to define the mechanisms of vaccine-induced B and T cell responses in clearing HIV-1 reservoirs. Additionally, novel therapies will be combined with the vaccines to augment clearance of HIV-1 reservoirs. In both FOCUS 1 and 2, analysis of the breakthrough and latent reservoir Env sequences will inform the design of new vaccine boosts for an improved protective vaccine regimen that can also limit rebound viruses. The NHP-SHIV Centralized Research Resource (CRR) will support the NHP studies in FOCUS 1 and 2 to investigate the effectiveness of vaccine-induced polyfunctional responses and novel immunotherapies in clearing HIV-1 reservoirs. These studies will use innovative barcoded-SHIVs to determine the effect of vaccine-induced responses on eliminating the viral reservoirs, and to evaluate the quantity and quality of viruses that are reactivated by latency reversing agents (LRAs) following treatment interruption. The Management and Operations Support Unit (MOS) will coordinate the scientific and administrative activities of this CIAVCR Program to ensure that the FOCI and NHP-SHIV CRR function cohesively. By the end of this grant, we expect to have designed a combined preventive and therapeutic approach to effectively protect from infection and eliminate viral reservoirs—a strategy for effectively impacting the HIV/AIDS pandemic.