Cell-Based Secretion of Antiviral Molecules as a Treatment for HIV-AIDS

描述（由申请人提供）：治疗慢性疾病（如艾滋病毒/艾滋病）的传统方法已被证明在治疗分子的施用和根除潜在疾病本身方面效率相对低下；虽然传统的抗逆转录病毒治疗（ART）可以抑制血浆病毒血症，但低水平的病毒复制仍然存在。我们最近的研究结果表明，用表达膜锚定融合抑制剂（mC46）的基因修饰的CD34+细胞移植的尾尾猕猴产生抗感染的CD4+ t细胞，维持正常的CD4+ t细胞水平，并对shiv攻击病毒产生增强的免疫反应，导致血浆病毒血症降低300- 1400倍。尽管这些结果非常令人鼓舞，但仍需要其他方法来进一步将血浆病毒血症降低到无法检测的水平和/或潜在地消除病毒库。因此，我们建议开发一种基于修饰造血干细胞（hsc）或CD4+ t细胞的新型递送系统，以便直接靶向体内的病毒库。使用原代细胞递送治疗性肽代表了一种创新和理想的模式，可以在整个患者体内系统地递送治疗性分子。此外，hsc衍生谱系跨越生理和解剖障碍的能力代表了这种疗法的独特潜力。低水平的植入可能会产生足够数量的分泌抗逆转录病毒肽，而摄取的效率将大大提高，因为在通常被认为维持持久病毒库的部位有连续的治疗分子来源。为了将前病毒靶向内切酶传递到潜伏库，最终分化的原代细胞，如CD4+ t细胞，在整个淋巴组织中迁移是理想的载体。因此，本研究的目的是探讨利用转基因造血干细胞和CD4+ t细胞分泌抗逆转录病毒分子来控制病毒复制并直接靶向体内潜伏库的可行性。

DESCRIPTION (provided by applicant): Conventional methods for treating chronic diseases such as HIV/AIDS have proven to be relatively inefficient both in terms of administration of therapeutic molecules and eradication of the underlying diseases themselves; while conventional antiretroviral therapy (ART) suppresses plasma viremia, low-level viral replication persist. Our recent findings have indicated that pigtailed macaques transplanted with gene-modified CD34+ cells expressing a membrane-anchored fusion inhibitor (mC46) develop infection-resistant CD4+ T-cells, maintain normal CD4+ T-cell levels, and develop an enhanced immune response against the SHIV-challenge virus resulting in a 300- to 1400-fold decrease in plasma viremia. Despite these very encouraging results, additional methods to further reduce plasma viremia to undetectable levels and/or potentially eliminate viral reservoirs will be required. Hence, we propose the development of a novel delivery system based on modifying hematopoietic stem cells (HSCs) or CD4+ T-cells in order to directly target viral reservoirs in vivo. The use of primary cells to deliver therapeutic peptides represents an innovative and ideal mode for systemically delivering therapeutic molecules throughout a patient's body. Furthermore, the ability of HSC-derived lineages to transverse both physiological and anatomical barriers represents a unique potential of this therapy. Low levels of engraftment would likely yield sufficient quantities of secreted antiretroviral peptides, while the efficiency f uptake would be greatly enhanced as there is a continuous source of the therapeutic molecules at sites typically thought to maintain persistent viral reservoirs. In order to deliver proviral targeting endonucleases to latent reservoirs, terminally differentiated primary cell such as CD4+ T-cells that migrate throughout lymphoid tissue represents the ideal vehicle. Hence, the goal of this study is to examine the feasibility of using genetically modified HSCs and CD4+ T-cells to secrete antiretroviral molecules to control viral replication and directly target latent reservoirsin vivo.