eCD4-mediated control of SIV infection in the brain

项目总结 联合抗逆转录病毒疗法(ART)使艾滋病毒的治疗发生了革命性的变化，但ART方案并没有 没有缺点。成本、日常管理的需要、副作用和社会耻辱都会导致 患者依从性降低。此外，尽管接受了治疗，大约15%-55%的艾滋病毒携带者仍将发展为 某种形式的艾滋病毒相关神经认知障碍(手)。 由于ART疗法的这些问题，我们和许多其他研究人员一直在研究这种疗法的使用 重组腺相关病毒(RAAV)基因治疗载体用于传递抗体和其他艾滋病毒 艾滋病毒携带者的治疗。因为这些向量的表达本质上是永久性的； 只需一种AAV疗法(即“功能性”治疗)，患者就可以终身免受艾滋病毒感染。 治愈)。尽管已经进行了大量的非人灵长类实验和两项人类临床试验 然而，为了研究AAV用于功能性治疗，我们不知道有任何努力来确定是否或 非rAAV表达的生物制品可以预防或治疗手部疾病。 我们已经开发出一种名为eCD4的抗HIV生物制剂，它是一种将CD4-Ig与羧基末端共受体融合在一起的化合物 (CCR5/CXCR4)模拟多肽。我们假设eCD4是唯一适合于防止复制的 优先感染大脑的嗜神经性HIV毒株(嗜巨噬细胞分离物)，因为这些 病毒必然会进化出对CD4的高亲和力，以补偿巨噬细胞上CD4的低丰度 和小胶质细胞。 因此，该项目的组织假设是确定rAAV传递的eCD4是否表达自 外周或中枢神经系统内，可预防或治疗手部疾病。为了检验这一假设，我们 将使用由SIV引起的中枢神经系统疾病的辫尾猕猴模型，该模型是在我们的 与免疫抑制群(SIV/DeltaB670)和嗜神经性克隆共同感染的实验室 (SIV/17E-Fr)建立了高度可重复性的中枢神经系统感染。动物将接受抗逆转录病毒治疗，直到无性系繁殖。 RAAV将被用来向骨骼肌和/或脑组织运送辫子猕猴版本的eCD4。 ART将被撤销，以确定rAAV/eCD4是否可以防止中枢神经系统病毒血症的再次出现。 如果成功，这些研究可能会为艾滋病毒的功能性治疗和手部疾病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.