Development of an mRNA-Based Therapeutic HIV/AIDS Vaccine

项目摘要 尽管联合抗逆转录病毒治疗（cART）的出现显着改善了 人类免疫缺陷病毒（HIV）感染者，单靠cART无法根除感染， 因此，必须终身维持每日治疗，以防止病毒复制失控的复发， 恢复疾病进展。然而，终身治疗对接受治疗的个人既有健康风险， 给社会带来巨大的经济负担。因此，迫切需要开发新的治疗药物。 治疗艾滋病毒的干预措施。由于大多数严格的、长期的、自发的和疫苗相关的 HIV和猴免疫缺陷病毒（SIV）感染免疫控制是已知的，或强烈怀疑的 由于CD 8 + T细胞介导，旨在利用CD 8 + T细胞免疫的治疗策略具有很大的前景 用于在不存在cART的情况下实现病毒复制的持久控制，通常被称为“功能性治愈”。 然而，在大多数人中，由HIV感染诱导的自然发生的CD 8 + T细胞应答通常是 无法有效控制病毒。因此，任何基于增强CD 8 + T细胞免疫力的HIV治疗策略， 将需要引发免疫应答，所述免疫应答在质量上和/或数量上不同于 在初次感染期间出现，随后在cART期间维持。此外，在治疗的背景下， 当有回弹能力的病毒储库全身分布时，具有高频率的效应子- 预先定位在潜在病毒感染位点的分化的和功能有效的抗病毒CD 8 + T细胞应答 cART停止时的反弹（即使在免疫豁免部位，如B细胞滤泡）可能是 对于实现持久的cART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是否 利用基于信使核糖核酸（mRNA）的疫苗平台RNActive RP 100的疫苗接种策略， 可以增强接受cART治疗的SIV感染恒河猴（RM）的细胞免疫，并建立高水平、长时间的 cART停止后SIV复制的长期控制。这个矢量的选择是基于初步的数据 证明了具有SIV基因插入物的RNActive疫苗（mRNA/SIV）在RM中具有高度免疫原性， 诱导具有广泛表位识别的有效的、全身分布的SIV特异性CD 8 + T细胞的能力。这里 我们将评估单独的mRNA/SIV疫苗接种或与抗CD 20 B细胞耗竭（以破坏 B细胞滤泡）可以促进立即拦截反弹的病毒储库，以促进持久控制 cART停止后SIV复制。在这个项目中发现的任何疫苗有效性都将提供强大的动力 用于在cART抑制的HIV+患者中对RNActive RP 4平台进行临床评估，并可能导致 临床上可转化的治疗方法，以实现cART后的HIV感染缓解。

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.