Targeting CD4 T follicular helper cells for enhancing HIV vaccine induced humoral immunity

项目摘要 抗逆转录病毒疗法（ART）通过使艾滋病 可以控制但仍无法治愈在全球实施抗逆转录病毒疗法方面存在重大障碍， 限制了其可持续预防艾滋病毒的效用。此外，与衰老有关的条件和 长期抗逆转录病毒治疗的后果将对医疗保健系统和艾滋病毒产生重大影响 患者这些挑战突出表明，需要采取既能提供可持续的艾滋病毒， 预防和功能性艾滋病毒治疗。RV144试验的结果表明，接种疫苗可以预防艾滋病毒 艾滋病病毒在人类中的传播和抗包膜（Env）HIV抗体的持久性可能是关键 保护对RV 144试验进行改进的努力表明，加强免疫接种增加了 血清抗Env抗体滴度仅为一过性。这种"抗Env抗体持久性问题"阻碍了我们的研究。 努力研制有效的艾滋病毒疫苗。这一建议旨在提高我们对功能的理解 免疫机制参与产生持久的HIV Env抗体，在全身和全身 直肠和阴道粘膜。为了实现这一点，我们将使用DNA-prime/Protein-boost 恒河猴的疫苗方案。本研究项目的目标1是确定Th1与 Th1/Th17启动影响先天性炎症反应、Env TFH频率、表型、转录谱， 和B细胞辅助能力，以及全身和粘膜抗Env抗体滴度。目标2将决定 无论是将现有技术的可溶性Env模拟物、Env SOSIP三聚体蛋白免疫原与高度特异性的免疫原结合， 有效和稳健的佐剂（诱导Th1/Th17应答，导致高质量、长时间的 相对于Th1疫苗方案的持久抗Env抗体。我们将进一步研究疫苗介导的 多功能TFH反应的诱导提高了面对粘膜类人猿HIV时的保护作用 挑战.这些临床前研究将建立机制和实验基础，以确定如何 TFH辅助细胞谱影响抗Env抗体寿命和疫苗效力， 为设计成功的艾滋病毒疫苗奠定了循证基础。

Project Summary Anti-retroviral therapy (ART) has dramatically altered the HIV pandemic landscape by rendering the disease manageable - but still incurable. Significant barriers are associated with the global implementation of ART that limit its utility for sustainable prevention of HIV. Moreover, the intersection of aging-related conditions and the consequences of long-term ART will have a substantial impact on the healthcare system as well as on HIV patients. These challenges underscore the need to pursue strategies that will provide both sustainable HIV prevention and a functional HIV cure. The results of the RV144 trial indicate that vaccination may prevent HIV transmission in humans and that durability of anti-envelope (Env) HIV antibodies may be the key to this protection. Efforts to improve upon the RV144 trial have demonstrated that booster immunizations increase serum anti-Env antibody titers only transiently. This “anti-Env antibody persistence problem” impedes our efforts to develop an effective HIV vaccine. This proposal is designed to improve our functional understanding of the immunological mechanism involved in producing durable HIV Env antibodies in both the systemic circulation and the rectal and vaginal mucosa. To accomplish this, we will be using a DNA-prime/Protein-boost vaccine regimen in rhesus macaques. Aim 1 of this research project is focused on establishing how Th1 versus Th1/Th17 priming impacts innate inflammatory response, Env TFH frequencies, phenotype, transcriptional profile, and B cell helper capacity, as well as systemic and mucosal anti-Env antibody titers. Aim 2 will determine whether combining the state-of-the-art soluble Env mimic, an Env SOSIP trimer protein immunogen with a highly potent and robust adjuvant (to induce Th1/Th17 response, results in increased production of a high-quality, long- lasting anti-Env antibodies relative to Th1 vaccine regimen. We will further investigate whether vaccine-mediated induction of the polyfunctional TFH response improves protection when faced with a mucosal simian HIV challenge. These preclinical studies will establish the mechanistic and experimental foundations to identify how TFH helper cell profiles impact anti-Env antibody longevity and vaccine efficacy and will lay the necessary, evidence-based foundation for the design of a successful HIV vaccine.