Development of an mRNA-Based Therapeutic HIV/AIDS Vaccine

项目总结 尽管联合抗逆转录病毒疗法(CART)的出现极大地改善了该病的预后 携带人类免疫缺陷病毒(HIV)的人，仅靠CART无法根除感染， 因此，必须终生维持日常治疗，以防止病毒复制失控和复发。 疾病进展的恢复。然而，终生治疗对接受治疗的人来说既有健康风险 给社会带来了巨大的经济负担。因此，迫切需要开发新的治疗方法。 治疗艾滋病毒的干预措施。因为大多数严格的、长期的、自发的和疫苗相关的例子 人类免疫缺陷病毒(HIV)和猴免疫缺陷病毒(SIV)感染的免疫控制是已知的或强烈怀疑的 以CD8 T细胞为中介，开发CD8 T细胞免疫的治疗策略大有可为 用于在没有CART的情况下实现对病毒复制的持久控制，通常被称为“功能治愈”。 然而，在大多数人中，艾滋病毒感染引起的自然产生的CD8 T细胞反应通常是 在控制病毒方面效果不佳。因此，任何基于增强CD8 T细胞免疫的HIV治愈策略 需要激发在质量和/或数量上不同于 在初次感染期间出现，随后在CART期间保持。此外，在治愈的背景下 反弹能力强的病毒库是系统分布的，具有高频率的效应器- 预先定位在潜在病毒部位的分化和功能强大的抗病毒CD8 T细胞反应 CART停止时的反弹(即使在免疫特权部位，如B细胞滤泡)很可能是 对于实现持久的购物车后病毒控制至关重要。在这个项目中，我们将确定一种治疗方法 利用基于信使核糖核酸的疫苗平台RNActive的疫苗接种策略， 可增强手推车上感染SIV的恒河猴(RM)的细胞免疫功能，建立高水平、长时间的 CART停止后SIV复制的长期控制。该向量的选择是基于初步数据 证明插入SIV基因的RNActive疫苗在RM中具有高度的免疫原性， 诱导强大的、系统分布的、具有广泛表位识别的SIV特异性CD8 T细胞的能力。这里 我们将评估是否单独接种mRNA/SIV疫苗或联合应用抗CD20 B细胞耗竭(以破坏 B细胞滤泡)可促进立即拦截反弹的病毒库，从而有助于持久控制 Cart停止后的SIV复制。该项目中任何疫苗功效的发现都将提供强大的推动力 用于临床评估CART抑制的艾滋病毒患者的RNActive平台，并可能导致 临床可转化的治疗方法，以实现艾滋病毒感染的缓解。

PROJECT SUMMARY Although the advent of combination antiretroviral therapy (cART) has dramatically improved the prognosis of people living with human immunodeficiency virus (HIV), cART alone cannot eradicate the infection and, therefore, daily treatment must be maintained for life to prevent relapse of uncontrolled viral replication and resumption of disease progression. However, lifelong treatment entails both health risks to treated individuals and a significant economic burden to society. As such, there is a pressing need to develop novel therapeutic interventions to cure HIV. Since most examples of stringent, long-term, spontaneous and vaccine-associated immune control of HIV and simian immunodeficiency virus (SIV) infection are either known, or strongly suspected to be CD8+ T cell-mediated, therapeutic strategies designed to exploit CD8+ T cell immunity hold great promise for achieving durable control of virus replication in the absence of cART, often referred to as a “functional cure”. However, in most people, naturally occurring CD8+ T cell responses induced by HIV infection are often ineffective at controlling the virus. As such, any HIV cure strategy based on enhancing CD8+ T cell immunity would need to elicit immune responses that are qualitatively and/or quantitatively different from those that emerge during primary infection and are subsequently maintained during cART. In addition, in the setting of cure where the rebound-competent viral reservoir is systemically distributed, having high frequencies of effector- differentiated and functionally potent anti-viral CD8+ T cell responses pre-positioned in sites of potential viral rebound (even in immune privileged sites such as B cell follicles) at the time of cART cessation is likely to be critical for achieving durable post-cART viral control. In this project, we will determine whether a therapeutic vaccination strategy that utilizes the messenger ribonucleic acid (mRNA)-based vaccine platform RNActive, can enhance cellular immunity in SIV-infected rhesus macaques (RM) on cART and establish high-level, long- term control of SIV replication after cART cessation. The choice of this vector is based on preliminary data demonstrating RNActivevaccines with SIV gene inserts (mRNA/SIV) are highly immunogenic in RM, with the capacity to elicit potent, systemically distributed, SIV-specific CD8+ T cells with broad epitope recognition. Here we will assess whether mRNA/SIV vaccination alone or in combination with anti-CD20 B cell depletion (to disrupt B cell follicles) can facilitate immediate interception of rebounding viral reservoirs to facilitate durable control of SIV replication after cART cessation. Any finding of vaccine efficacy in this project will provide strong impetus for clinical assessment of the RNActiveplatform in cART-suppressed HIV+ patients and potentially lead to a clinically translatable therapeutic approach to achieve HIV infection remission off cART.