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。艾滋病毒治疗方面的进展是无可争议的，具有强大的效力 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，同时 正在接受治疗。尽管CART可以将血浆HIV病毒抑制维持在无法检测的水平， 停用CART总是会导致血浆病毒血症迅速反弹。Cart无法治愈艾滋病毒是 至少部分是由于持久的艾滋病毒宿主，如在中枢神经系统的那些，以及大多数人的能力有限 跨越血脑屏障的艺术。此外，由于大脑中的活跃感染，高达50%的 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- 相关神经认知障碍(手)。我们的长期目标是控制艾滋病毒在中枢神经系统的复制，并 治疗或预防艾滋病毒携带者的手牵手(PLWH)。寻找更具效力的新治疗剂 而且正在产生的不良影响也在减少。例如，广泛的艾滋病毒中和抗体(BNAbs)是一种新的 最近公认的可消除病毒血症的治疗方法。尽管如此，由于它们的体积很大，这些生物制品 在全身给药后，甚至比CART更不可能到达大脑。因此，便利的工具 这些有效和安全的药物对大脑的有效和持久的给药是迫切需要的，因为 它们可以解决大脑中艾滋病毒储存库这一具有挑战性的问题。这项提案的目标是控制艾滋病毒 通过持续递送bNAbs在大脑中复制。因此，这一提议是基于以下前提 CART无法抑制HIV在中枢神经系统的复制可以通过一种补充策略来克服，即 在大脑中持续释放高效的bNAbs。因此，我们假设 体外工程神经胶质细胞在脑内持续释放基因编码的HIV bNAbs 祖细胞(GRPs)可以抑制HIV复制，减少HIV诱导的神经病变。 我们组建了一个跨学科的团队，他们的专长是(I)在小鼠身上建立艾滋病毒模型；(Ii)开发艾滋病毒 BNAbs；(3)基于干细胞的治疗和干细胞的基因工程；(4)影像引导动脉内 注射将全球细胞输送到大脑。在我们的初步工作中，我们已经表明动脉内 运送的GRPs可以穿过血脑屏障，可能成为当地产生艾滋病毒的携带者 脑实质中的bNAbs。在我们建议的研究中使用GRP的主要优势是它们的健壮性 植入，向少突胶质细胞和星形胶质细胞分化，以及在大脑中持续数月 甚至在移植后数年。因此，它将满足bNAbs产生长期影响的需要 防止艾滋病毒在中枢神经系统复制，并可能有助于根除中枢神经系统艾滋病毒的蓄积物。 总体而言，我们提出了一种创新的基于细胞的策略，以解决药物在整个 血脑屏障，控制和根除中枢神经系统中的艾滋病毒宿主。如果我们的项目证明了安全性 它可能会迅速转化为临床环境，对许多PLWH产生深远影响。

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.