Image-guided intra-arterial administration of antibody-releasing glial progenitors to control the HIV CNS reservoir.

本提案响应RFA DA-22-010。艾滋病毒治疗的进展是无可争议的， 联合抗逆转录病毒疗法（cART），使大多数人能够相对健康地生活几十年， 接受治疗尽管cART可以将血浆HIV病毒抑制维持在不可检测的水平， 停止cART总是导致血浆病毒血症的快速反弹。cART无法治愈艾滋病毒， 至少部分是由于持续的HIV储存库，如CNS中的那些，以及大多数人的能力有限。 通过血脑屏障。此外，由于大脑中的活动性感染， 感染者可能会出现一系列认知、运动和/或情绪问题，统称为HIV-1， 相关神经认知障碍（HAND）。我们的长期目标是控制中枢神经系统中的HIV复制， 治疗或预防艾滋病毒感染者（PLWH）的HAND。寻找更有效的新治疗药物 不良影响也在减少。例如，广泛的HIV中和抗体（bNAb）是一种新的免疫抑制剂。 这类疗法最近被认为可以消除病毒血症。尽管如此，由于它们的大尺寸，这些生物制剂 甚至比cART更不可能在全身给药后到达大脑。因此，这些工具 迫切需要将这些有效且安全的药物有效且持久地施用到大脑 他们可以解决大脑中HIV储存库的难题。这项提案的目标是控制艾滋病毒 因此，该提议基于以下前提： cART不能抑制HIV在CNS中的复制可以通过补充策略来克服，该策略 在大脑中持续释放高效的bNAb。因此，我们假设， 通过离体工程化和移植的胶质细胞在脑中持续释放遗传编码的HIV bNAb 祖细胞（GRP）可以抑制HIV复制并减少HIV诱导的神经发病。 我们组建了一个跨学科的团队，他们具有以下方面的专业知识：（i）在小鼠中建立HIV模型;（ii）开发HIV bNAB;（iii）干细胞治疗和干细胞基因工程;（iv）图像引导动脉内 注射用于向大脑的整体细胞递送。在我们的初步工作中，我们已经表明，动脉内 递送的GRP可以穿过血脑屏障，潜在地充当HIV局部产生的载体 脑实质中的bNAb。在我们提出的研究中使用GRP的主要优点是它们的鲁棒性 移植，向少突胶质细胞和星形胶质细胞分化，并在脑中持续数月 甚至在移植后数年。因此，它将满足bNAB引起的持久作用的需要， 防止HIV在CNS中复制，并可能有助于根除HIV的CNS储库。 总的来说，我们提出了一种创新的基于细胞的策略，解决了药物渗透性差的问题。 血脑屏障，以控制和消除中枢神经系统中的艾滋病毒水库。如果我们的项目证明安全 和疗效，它可以迅速转化为临床环境，深刻影响许多PLWH。

This proposal responds to RFA DA-22-010. Progress in the treatment of HIV is undisputed with potent combined antiretroviral therapy (cART), allowing most individuals to live relatively healthy for decades while receiving treatment. Although cART can maintain plasma HIV viral suppression to undetectable levels, discontinuation of cART invariably results in a rapid rebound of plasma viremia. cART’s inability to cure HIV is due, at least in part, to persistent HIV reservoirs, such as those in the CNS, and to the limited ability of most ARTs to cross the blood-brain barrier. In addition, because of active infection in the brain, up to 50% of those infected may develop a spectrum of cognitive, motor, and/or mood problems collectively known as HIV- Associated Neurocognitive Disorder (HAND). Our long-term goal is to control HIV replication in CNS and to treat or prevent HAND in people living with HIV (PLWH). Search for new therapeutic agents with more potency and fewer adverse effects is underway. For example, broadly HIV-neutralizing antibodies (bNAbs) are a new class of therapeutics recently recognized to eliminate viremia. Still, due to their large size, these biologics are even less likely than cART to reach the brain after systemic administration. Therefore, the tools that facilitate the effective and long-lasting administration of these potent and safe drugs to the brain are urgently needed as they can solve the challenging problem of the brain’s HIV reservoir. The goal of this proposal is to control HIV replication in the brain by sustained delivery of bNAbs.Therefore, this proposal is based on the premise that the inability of cART to inhibit HIV replication in the CNS can be overcome by a complementary strategy that provides sustained release of highly efficacious bNAbs in the brain. Accordingly, we hypothesize that sustained release of genetically-encoded HIV bNAbs in the brain by ex vivo engineered and transplanted glial progenitor cells (GRPs) can suppress HIV replication and decrease HIV-induced neuropathogenesis. We assembled an interdisciplinary team with expertise in (i) modeling HIV in mice; (ii) developing HIV bNABs; (iii) stem cell-based therapy and genetic engineering of stem cells; (iv) image-guided intraarterial injection for global cell delivery to the brain. In our preliminary work, we have shown that intra-arterially delivered GRPs can cross the blood-brain barrier, potentially serving as carriers for local production of HIV bNAbs in brain parenchyma. The main advantage of using GRPs in our proposed studies is their robust engraftment, differentiation towards oligodendrocytes and astrocytes, and persistence in the brain for months and even years after transplantation. Thus, it will meet the need for long-lasting effects elicited by bNABs to prevent HIV replication in the CNS and may help eradicate the CNS reservoir of HIV. Overall, we propose an innovative cell-based strategy that addresses poor drug penetration across the blood-brain barrier to control and eradicate the HIV reservoir in the CNS. If our project demonstrates safety and efficacy, it could be rapidly translated into the clinical settings, profoundly impacting many PLWH.