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

摘要 现在有大量证据表明，艾滋病毒感染者患严重疾病的风险显着增加 感染SARS-CoV-2时的COVID-19疾病。此外，使用和注射毒品的人（PWUD和 PWID）感染艾滋病毒和接触SARS-CoV-2的风险很高，在获得治疗方面面临重大障碍。 抗病毒疗法（即，通常是免疫受损的）。这一问题进一步加剧， SARS-CoV-2变异体逃避疫苗介导的免疫-现在很明显， 个体促进SARS-CoV-2逃逸变异体和HIV感染的PWUD/PWID的进化 这样的治疗方法代表了这样一个群体。因此，对于新的药物存在严重的未满足的医疗需求。 可以治疗HIV和SARS-CoV-2的治疗方法-特别是关注的新变种-以及 可以有效地部署在难以到达的高风险人群中（例如，PWUD/PWID）。远景目标 这项工作的重点是开发针对HIV-1和SARS-CoV-2变体的单次给药疗法， PWID/PWUD人群。这项补充建议的具体目的是测试我们最近推出的 在来自HIV+ PWID的患者细胞中开发了针对HIV和SARS-CoV-2变体的基因驱动疗法（GDT）。 这项工作将在我们最近成功设计HIV-1（见父母奖）和寨卡病毒的GDT的基础上再接再厉 病毒（ZIKV），以及我们广泛的初步体外数据显示GDT对SARS-CoV-2的疗效 变体。基于我们广泛的初步体外研究，中心假设是我们的工程化 GDT候选人将有能力降低SARS-CoV-2病毒载量和致病性，包括 关注的SARS-CoV-2变体和HIV病毒载量，从而作为单次给药， 治疗HIV-1和SARS-CoV-2。SARS-CoV-2 GDT的基本原理是基于我们的初步研究。 数据显示，GDT显着减少SARS-CoV-2在细胞培养中的复制， CoV-2变异体以及在人源化小鼠中对HIV-1的广泛研究和FDA会议的阳性结果。我们将 通过两个具体目标实现我们的目标：（i）量化最近开发的GDT在体内的功效， 减少SARS-CoV-2病毒在仓鼠中的复制和致病性;和（ii）开发肺类器官共 培养以测试GDT在来自HIV+ PWID的患者来源的细胞中针对HIV-1和SARS-CoV-2的功效。而 GDT方法具有固有的风险，单次给药疗法对SARS-CoV-2和 因此，这种方法将非常有益，特别是对于治疗难以接触的高风险PWID人群。 本文的研究也将通过建立一种新的文化模式而具有广泛的基础性意义 和工具来分析SARS-CoV-2和HIV感染如何在PWUD/PWID环境中相互作用（即，背景下 物质使用障碍（SUD）的风险人群），并将提供一种新的医疗 针对新出现的SARS-CoV-2变异体的治疗效果的对策。

ABSTRACT Substantial evidence now indicates that HIV-infected individuals are at a significantly elevated risk for severe COVID-19 disease when infected with SARS-CoV-2. Moreover, persons who use and inject drugs (PWUD and PWID) have a high-risk of HIV infection and exposure to SARS-CoV-2 and face major barriers to accessing antiviral therapies (i.e., are often immunocompromised). The problem is further exacerbated by the emergence of SARS-CoV-2 variants that escape vaccine-mediated immunity—it is now evident that immunocompromised individuals promote the evolution of SARS-CoV-2 escape variants and HIV-infected PWUD/PWID with barriers to treatment represent such a population. Consequently, there is a critical unmet medical need for new therapeutics that could treat HIV as well as SARS-CoV-2—particularly the emerging variants of concern’—and could be effectively deployed in difficult-to-reach, high-risk populations (e.g., PWUD/PWID). The long-term goal of this work is to develop single-administration therapies for HIV-1 and SARS-CoV-2 variants to effectively reach PWID/PWUD populations. The specific objective of this supplement proposal is to test efficacy of our recently developed Gene Drive Therapies (GDT) against HIV and SARS-CoV-2 variants in patient cells from HIV+ PWID. This effort will build heavily off our recent success in engineering GDTs for HIV-1 (see Parent Award) and Zika Virus (ZIKV), as well as our extensive preliminary in vitro data showing efficacy of GDTs against SARS-CoV-2 variants. The central hypothesis—based on our extensive preliminary in vitro studies—is that our engineered GDT candidates will have the capacity to reduce both SARS-CoV-2 viral load and pathogenesis, including of SARS-CoV-2 variants of concern, and HIV viral load, thereby serving as a single-administration, combination therapeutic for HIV-1 and SARS-CoV-2. The rationale for a GDT for SARS-CoV-2 is based on our preliminary data showing that GDTs significantly reduce SARS-CoV-2 replication in cell culture, are equally effective against CoV-2 variants and from extensive studies on HIV-1 in humanized mice and positive FDA meetings. We will achieve our objectives via two specific aims: (i) Quantify in vivo efficacy of the recently developed GDT in reducing SARS-CoV-2 viral replication and pathogenesis in hamsters; and (ii) Develop a lung-organoid co- culture to test efficacy of GDTs against HIV-1 and SARS-CoV-2 in patient-derived cells from HIV+ PWIDs. While the GDT approach carries inherent risks, single-administration therapeutics active against both SARS-CoV-2 variants and HIV would be highly beneficial, particularly for treating difficult-to-reach, high-risk PWID populations. The studies proposed here will also have broad fundamental significance by establishing a novel culture model and tool to assay how SARS-CoV-2 and HIV infections interact in the PWUD/PWID setting (i.e., in the context of Substance Use Disorders (SUDs) in at-risk populations) and will provide in vivo validation of a novel medical countermeasure with therapeutic efficacy against emerging SARS-CoV-2 variants.