eCD4-mediated control of SIV infection in the brain

项目摘要 联合抗逆转录病毒疗法（ART）已经彻底改变了艾滋病毒的治疗，但ART方案并没有 没有缺点。费用、每日用药的需要、副作用和社会耻辱都有助于 降低患者依从性。此外，尽管接受了治疗，但仍有15-55%的艾滋病毒感染者会发展为 某种形式的HIV相关神经认知障碍（HAND）。 由于ART方案存在这些问题，我们和许多其他研究人员一直在研究使用 重组腺相关病毒（rAAV）基因治疗载体， 艾滋病病毒感染者的治疗方法。因为这些载体的表达基本上是永久性的; 仅用单一AAV治疗（即“功能性”AAV治疗）就可以保护患者终身免受HIV感染。 治愈）。尽管已经进行了许多非人类灵长类动物实验和两项人类临床试验， 研究使用AAV进行功能性治疗，然而，我们不知道有任何努力来确定是否或 不是rAAV表达的生物制剂可以预防或治疗HAND。 我们已经开发了一种称为eCD 4的抗HIV生物制剂，它是CD 4-IG与羧基末端辅助受体的融合物 (CCR5/CXCR 4）模拟肽。我们假设eCD 4是唯一适合于防止复制， HIV的嗜神经株优先感染大脑（嗜巨噬细胞分离株），因为这些 病毒必然进化出对CD 4的高亲和力以补偿巨噬细胞上CD 4的低丰度 和小胶质细胞。 因此，该项目的组织假设是确定rAAV递送的eCD 4，无论是从 外周或中枢神经系统内，可以预防或治疗手。为了验证这个假设，我们 将使用猪流感病毒引起的中枢神经系统疾病的猪尾猕猴模型， 实验室，其中与免疫抑制群（SIV/DeltaB 670）和嗜神经性克隆共感染 (SIV/17 E-Fr）建立了高度可再现的CNS感染。动物将接受ART治疗，直至出现禽流感 rAAV将用于将猪尾猕猴形式的eCD 4递送至骨骼肌和/或脑组织。 ART将被撤回，以确定rAAV/eCD 4是否可以预防CNS病毒血症的再次出现。 如果成功，这些研究可能为HIV的功能性治愈和HAND的治疗开辟新的途径。

PROJECT SUMMARY Combined antiretroviral therapy (ART) has revolutionized the treatment of HIV but ART regimens are not without drawbacks. Cost, the need for daily administration, side effects, and social stigma all contribute to reduced patient compliance. Moreover, despite treatment, some 15-55% of people living with HIV will develop some form of HIV-associated neurocognitive disorder (HAND). Because of these problems with ART regimens, we and many other investigators have been studying the use of recombinant adeno-associated virus (rAAV) gene therapy vectors to deliver antibodies and other HIV therapeutics to people living with HIV. Because expression from these vectors is essentially permanent; patients could be protected for life from HIV infections with only a single AAV treatment (i.e. a ‘functional’ cure). Although numerous nonhuman primate experiments and two human clinical trials have been conducted to study the use of AAV for functional cure, however, we are unaware of any efforts to determine whether or not rAAV-expressed biologics can prevent or treat HAND. We have developed an anti-HIV biologic called eCD4, a fusion of CD4-Ig with a carboxy-terminal co-receptor (CCR5/CXCR4) mimetic peptide. We hypothesize that eCD4 is uniquely suited to preventing replication of the neurotropic strains of HIV that preferentially infect the brain (macrophage-tropic isolates) because these viruses necessarily evolve high affinity for CD4 to compensate for the low abundance of CD4 on macrophages and microglia. The organizing hypothesis of this project, then, is to determine if rAAV-delivered eCD4, either expressed from the periphery or within the central nervous system, can prevent or treat HAND. To test this hypothesis, we will use a pigtail macaque model of SIV-induced central nervous system disease, developed in our laboratories, in which co-infection with an immunosuppressive swarm (SIV/DeltaB670) and neurotropic clone (SIV/17E-Fr) establishes a highly reproducible CNS infection. Animals will be treated with ART until aviremic and rAAV will be used to deliver a pigtail macaque version of eCD4 to skeletal muscle and/or brain tissue. ART will be withdrawn to determine whether or not rAAV/eCD4 can prevent the re-emergence of CNS viremia. If successful, these studies may open new avenues to the functional cure of HIV and treatment of HAND.