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

摘要 大量证据现在表明，艾滋病毒感染者患上严重的 新冠肺炎感染SARS-CoV-2时的疾病。此外，使用和注射毒品的人(PWUD和 PWID)有感染艾滋病毒和接触SARS-CoV-2的高风险，并面临重大障碍 抗病毒治疗(即，通常免疫功能受损)。这个问题的出现使问题进一步恶化。 逃脱疫苗介导免疫的SARS-CoV-2变种-现在很明显，免疫受损 个体通过屏障促进SARS-CoV-2逃逸变异和HIV感染PWUD/PWID的进化 治疗代表了这样一个人群。因此，存在着对新的、尚未得到满足的医疗需求 可以治疗艾滋病毒和SARS-CoV-2的治疗方法--特别是令人担忧的新变种--以及 可以有效地部署在难以接触到的高危人群(例如，PWUD/PWID)中。长期目标 这项工作的重点是开发针对HIV-1和SARS-CoV-2变种的单一给药疗法，以有效地 PWID/PWUD人群。这项补充建议的具体目的是测试我们最近 针对HIV PWID患者细胞中的HIV和SARS-CoV-2变种开发了基因驱动疗法(GDT)。 这一努力将在很大程度上建立在我们最近在针对HIV-1(见家长奖)和寨卡病毒的GDT工程方面取得的成功的基础上 病毒(ZIKV)，以及我们广泛的体外初步数据显示GDT对SARS-CoV-2的有效性 变种。基于我们广泛的初步体外研究的中心假设是，我们的基因工程 GDT候选者将有能力降低SARS-CoV-2病毒载量和致病性，包括 SARS-CoV-2变异株的关注，以及艾滋病毒病毒载量，从而起到单一管理、组合的作用 治疗HIV-1和SARS-CoV-2。对SARS-CoV-2进行GDT的理由是基于我们的初步研究 数据显示，GDT显著减少细胞培养中SARS-CoV-2的复制，对 CoV-2变种，来自人源化小鼠对HIV-1的广泛研究，以及FDA会议呈阳性。我们会 通过两个具体目标实现我们的目标：(I)量化最近开发的GDT在体内的疗效 减少SARS-CoV-2病毒在仓鼠体内的复制和致病作用；以及(Ii)开发一种肺-器官联合- 在HIV PWID患者来源的细胞中培养GDT，以测试GDT对HIV-1和SARS-CoV-2的有效性。而当 GDT方法具有固有的风险，单一给药疗法对SARS-CoV-2有效 变种和艾滋病毒将是非常有益的，特别是对于治疗难以接触到的高危PWID人群。 本文提出的研究也将通过建立一个新的文化模型而具有广泛的基础性意义。 和分析SARS-CoV-2和HIV感染在PWUD/PWID环境中(即，在上下文中)如何相互作用的工具 高危人群中物质使用障碍(SOD)的研究)，并将提供一种新的医学方法的体内验证 针对新出现的SARS-CoV-2变异株的治疗效果对策。

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.