Targeted delivery of cytopathicity enhancing agents, and co-ordination with shock and kill, to reduce HIV reservoirs

项目摘要 尽管现代疗法极大地改善了人们的生活面貌 感染艾滋病毒后，他们无法治愈感染，这让这些人背负着 终身致力于抗逆转录病毒(ARV)药物治疗。对于任何给定的个人， 保持终生坚持服药可能会带来巨大的挑战。 此外，这些昂贵的药物对许多人来说是无法获得的，在 特别是那些处于资源匮乏环境中的人。因此，它将具有巨大的价值 开发新的疗法，可以使艾滋病毒进入缓解状态，我们所说的缓解状态是指 即使停止服用抗逆转录病毒病毒，病毒水平仍然很低或检测不到 药物治疗。目前，还没有这样的治疗性干预措施。最近的研究表明 研究表明，一种名为bcl2/bclxl拮抗剂的分子能够促进 感染艾滋病毒的细胞死亡，这可能导致病情缓解。这些令人担忧的问题 然而，BCL-2/BCL-XL拮抗剂与副作用有关， 很可能被认为是不可接受的。与此相关的是，这些分子并不是高度 对感染艾滋病毒的细胞具有特异性，也可导致一些未感染的人死亡 “旁观者”细胞。我们已经开发了一种技术，可以选择性地瞄准 将载药金纳米颗粒植入体内的某些细胞群体。在当前 我们的目标是利用这项技术更有选择性地靶向bcl2/bclxl 对受感染细胞群体的拮抗剂。在目标2中，这一目标将相对广泛- 例如，以所有记忆的CD4T细胞为靶点。在目标3中，我们将测试以下方法 专门针对仅感染艾滋病毒的细胞进行递送。对于这两种方法 可能还需要‘潜伏期反转剂(LRA)’来诱导HIV的某些表达 并促进受感染细胞的死亡。在AIM 2中，这些LRA将与 Bcl2/bclxl拮抗剂Be共负载金纳米粒子。在《目标3》中，LRA将成为 首先提供以诱导HIV表达，从而允许随后的特定靶向 BCL-2/BCL-XL拮抗剂对HIV感染细胞的作用。我们的提案将把这两个都包括在内 从体外实验到体内临床前的互补方法 模特。我们的最终目标是观察开发的新疗法的疗效。 在这些临床前模型中通过这个项目。如果观察到，这将使未来的临床 这些新疗法在艾滋病毒携带者身上的试验，可能会导致病毒感染 缓解，不需要持续的抗逆转录病毒治疗。

Project Abstract Although modern therapies have dramatically improved the outlooks for people living with HIV they are unable to cure infection, leaving these individuals burdened by a lifelong commitment to antiretroviral (ARV) medication. For any given individual, maintaining lifelong adherence to medication can present substantial challenges. Moreover, these expensive medications are not accessible for many individuals, in particular those in resource poor settings. It would therefore be of tremendous value to develop novel therapies that can drive HIV into remission, by which we mean into a state where levels of virus remain low or undetectable even when one stops taking ARV medication. At present, no such therapeutic intervention exists. Recent studies have shown that a type of molecule called BCL-2/BCL-XL antagonists is able to promote the death of HIV-infected cells, which could potentially lead to remission. A concern of these BCL-2/BCL-XL antagonists, however, is that they are associated with side-effects that are likely to be considered unacceptable. Relatedly, these molecules are not highly specific to HIV-infected cells and can also cause the death of some uninfected 'bystander' cells. We have developed a technology that allows for the selective targeting of drug-loaded gold nanoparticles to certain cell populations in vivo. In the current proposal we aim to use this technology to more selectively target BCL-2/BCL-XL antagonists to infected cell populations. In Aim 2, this targeting will be relatively broad – for example, targeting all memory CD4+ T-cells. In Aim 3, we will test approaches to specifically target delivery to only HIV infected cells. For both of these approaches 'latency reversing agents (LRAs)' may also be needed to induce some expression of HIV and promote the death of infected cells. In Aim 2, these LRAs will be provided along with BCL-2/BCL-XL antagonist be co-loading gold nanoparticles. In Aim 3, LRAs will be provided first in order to induce HIV expression, allowing subsequent specific targeting of BCL-2/BCL-XL antagonists to HIV-infected cells. Our proposal will take both of these complementary approaches from in vitro experiments through to an in vivo preclinical model. Our ultimate objective is to observe efficacy of the novel therapeutics developed by this project in these preclinical models. If observed, this would enable future clinical trials of these new therapies in people living with HIV, and potentially leading to viral remission without the need for ongoing ARV therapy.