A Gene Drive Therapy for HIV: single-administration intervention for high-risk groups

！ 项目概要 流行病学家早就认识到针对高风险“核心群体”的巨大潜力， 有效控制传染病的“超级传播者”。对于艾滋病毒/艾滋病，高危行为，例如个人 注射吸毒者（注射吸毒者）和女性性工作者，建立传播疾病的超级传播者核心群体 印第安纳州斯科特县注射吸毒者中艾滋病毒的爆发就是一个例子（Peters 等，NEJM 2016； 坎贝尔等人。 JID 2017）。如果未能针对这些群体采取疾病控制措施，就会大大削弱 遏制艾滋病毒爆发和降低发病率的能力（联合国艾滋病规划署全球艾滋病最新动态，2019 年）。不幸的是， 尽管有巨大的潜在好处，但针对这些高危人群采取疾病控制措施往往并不可行。 由于实现这些目标的成本和努力都很高，因此在实践中是可行的（Maxmen Nature，2018）。 为了覆盖这些关键人群，该项目将利用基因驱动技术（国家 科学院，2016 年报告）。基因驱动器是经过设计的合成结构，可在关键区域内扩展 人群，从基因上取代病原体，从而控制疾病传播。现代基因驱动—— 基于 Cas9——目前正在布基纳法索、巴西和其他地区进行控制疟疾的现场试验。的 HIV 基因驱动的基本原理基于我们广泛的初步研究，表明原型 HIV 基因 驱动器已在人源化小鼠中表现出功效，并且可以构成单次给药干预措施 具有很高的耐药性（Tanner 等人，《自然》，评论中）。流行病学分析表明，基因 驱动力将通过与艾滋病毒相同的风险因素在高危艾滋病毒感染群体中传播。特别是，对于 吸毒者注射毒品的使用——当多种艾滋病病毒变异体同时传播时——基因驱动平台将是独一无二的 适合克服现有的目标障碍并精确到达那些最难到达的超级传播者。 该提案将测试艾滋病毒基因驱动的原型。首先，原型基因驱动器将在患者身上进行测试 来自注射吸毒者的细胞，以验证原代细胞和人源化小鼠的初步体外功效。第二， 已建立的 HIV 感染非人类灵长类动物 (NHP) 模型将用于分析安全性（免疫原性和 基因毒性）、功效以及基因驱动在感染 HIV 的吸毒者中扩展和传播的潜力 使用注射药物的人群在 NHP 中使用动物间传播模型。最后，根据我们的 积极的人源化小鼠数据和现有的临床试验先例（例如，NCT03617198，一项为期 24 周的 ATI 试验 基于人源化小鼠数据获得批准）我们将启动早期 I/0 期临床干预试验 临终艾滋病毒队列（最后的礼物队列，吸毒人群）。该试验将测试该药物的安全性和有效性 HIV 基因驱动降低设定点病毒血症。总的来说，这些研究将推动基因驱动的发展 针对高风险吸毒人群的技术。最终，艾滋病毒基因驱动可以补充并充当 一个整合现有基因治疗方法（例如 RNAi、eCD4 等）的平台，从而产生高 目标控制的效率效益，无需识别和接触高风险群体的成本和挑战。

! Project Summary Epidemiologists have long recognized the immense potential of targeting high-risk ‘core groups’ and ‘superspreaders’ to efficiently control infectious diseases. For HIV/AIDS, high-risk behaviors, such as in persons who inject drugs (PWID) and female sex workers, establish core groups of superspreaders that drive disease spread, exemplified by the HIV outbreak among PWID in Scott County, Indiana (Peters et al. NEJM 2016; Campbell et al. JID 2017). Failure to target disease-control measures to these groups substantially weakens the ability to contain HIV outbreaks and reduce incidence (UNAIDS Global AIDS Update, 2019). Unfortunately, despite tremendous potential benefits, targeting disease-control measures to these high-risk groups is often not feasible in practice due to the high cost and effort of reaching them (Maxmen Nature, 2018). To reach these key populations, this project will capitalize on gene drive technologies (National Academy of Sciences, 2016 report). Gene drives are synthetic constructs engineered to expand within key populations, genetically displace the pathogen, and thereby control disease spread. Modern gene drives— based upon Cas9—are currently in field trials to control malaria in Burkina Faso, Brazil, and other locations. The rationale for an HIV gene drive is based upon our extensive preliminary studies showing that prototype HIV gene drives have demonstrated efficacy in humanized mice and could constitute single-administration interventions with a high barrier to resistance (Tanner et al, Nature, in review). Epidemiological analyses indicate that gene drives would spread through high-risk HIV-infected groups via the same risk factors as HIV. In particular, for injection drug use in PWID—when multiple HIV variants co-transmit—gene-drive platforms would be uniquely suited to overcome existing targeting obstacles and reach precisely those hardest-to-reach superspreaders. This proposal will test a prototype gene drive for HIV. First, prototype gene drives will be tested in patient cells from PWID to validate preliminary in vitro efficacy in primary cells and humanized mice. Second, established non-human primate (NHP) models of HIV infection will be used to assay safety (immunogenicity and genotoxicity), efficacy, and the potential of gene drives to expand and transmit within HIV-infected PWID populations using an injection drug use animal-to-animal transmission model in NHPs. Finally, based on our positive humanized-mouse data and existing clinical trial precedents (e.g., NCT03617198, a 24-week ATI trial that was approved based on humanized-mouse data) we will initiate an early Phase-I/0 clinical intervention trial in an end-of-life HIV cohort (Last Gift cohort, a drug-use population). This trial will test safety and efficacy of the HIV gene drive in lowering set-point viremia. Overall, these studies will propel development of gene drive technologies to target high-risk PWID populations. Ultimately, HIV gene drives could complement and serve as a platform to incorporate existing gene-therapy approaches (e.g. RNAi, eCD4, etc.), thereby yielding the high- efficiency benefits of targeted control without the cost and challenge of identifying and reaching high-risk groups.