Antibody-based eradication of HIV from the CNS reservoirs

尽管通过联合抗逆转录病毒疗法(CART)成功地控制了艾滋病毒，但艾滋病毒感染者仍在继续 在他们的大脑中藏匿艾滋病毒，并有患艾滋病毒相关神经认知障碍(手)的风险。这在一定程度上 由于CART对中枢神经系统的穿透不完全。然而，CART对脑组织的毒性也与此有关 用手。因此，为了在不引起毒性的情况下治疗中枢神经系统的HIV，新的治疗方法是必要的。最近，一位 新的广中和抗HIV单抗PGT121被证明能够控制 感染人类免疫缺陷病毒(SHIV)的恒河猴血液中的病毒复制。 然而，只有有限数量的PGT121可以穿透血脑屏障，而且它也不是 已知PGT121是否在CNS环境中保留其功能。我们的总体目标是减少病毒载量 通过重新设计PGT121来改善CSN，以更好地穿透BBB。我们将创造一种双特异性抗体，其中 PGT121是抗体的一只手臂，另一只手臂与血脑屏障上的人转铁蛋白受体(HTfR)结合 以促进主动跨细胞反应(PGT121/抗HTfR抗体)。中心假设是静脉输液与 PGT121/抗HTfR抗体将针对中枢神经系统中的HIV。我们的初步数据显示明显的脑脊液 直肠内感染后早期脑组织中猴免疫缺陷病毒(SIV)的检测和免疫球蛋白谱 不到0.2%的静脉输注的PGT121进入脑脊液，低于 疗效的阈值。我们推测，重组PGT121作为双特异性抗体(PGT121/抗hTfR抗体)可用于 有效地跨越BBB将通过减少病毒载量来治疗HAND，而不会产生与CART相关的毒性。我们会 通过追求三个具体目标来检验这一假设： 1)将单抗PGT121重新设计为双功能单抗，以改善中枢神经系统的穿透能力。 2.)双特异性PGT121/抗HTfR单抗治疗新城疫病毒感染的初步疗效和安全性 恒河猴。 3.)双特异性PGT121/抗SHV抗体降低感染恒河猴中枢神经系统贮备库中SHV的复制 HTfR抗体。 为了实现这些，TAN实验室将继续我们与雷曼实验室正在进行的合作，产生和 AIM中双特异性抗体PGT121/抗HTfR Ab的检测--1.AIM 2和3中非人灵长类的研究 将在Tan和Barouch实验室的合作下开发和实施。最新进展 双特异性抗体等新工具的问世将为发现新的治疗方法铺平道路 从中枢神经系统根除艾滋病毒。 这项拟议的工作将扩大我们对中枢神经系统内抗体介导的反应的理解，并创造 针对中枢神经系统艾滋病毒的新治疗干预措施。

Despite successful control of HIV with combined antiretroviral therapy (cART), HIV-infected patients continue to harbor HIV in their brain and are at risk for HIV-associated neurocognitive disorders (HAND). This is in part due to the incomplete CNS penetrations by cART. However, cART toxicity to the brain tissue is also associated with HAND. Therefore, novel therapy is necessary to treat HIV in the CNS without causing toxicity. Recently, a new broadly neutralizing monoclonal antibody (mAb) against HIV, PGT121, was shown to achieve control of viral replication in the blood of simian human immunodeficiency virus (SHIV)-infected Rhesus monkeys. However, only limited quantity of PGT121 penetrates through the blood-brain-barrier (BBB); and it is also not known if PGT121 retains its functions in the CNS environment. Our overall goal is to reduce viral load in the CSN by re-engineer PGT121 for better penetration through the BBB. We will create a bispecific antibody where PGT121 is one arm of the antibody and the other arm binds the human transferrin receptor (HTfR) on the BBB to facilitate active transcytosis (PGT121/anti-HTfR Ab). The central hypothesis is that intravenous infusion with PGT121/anti-HTfR Ab will specifically target HIV in the CNS. Our Preliminary Data demonstrated distinct CSF IgG profile, detection of simian immunodeficiency virus (SIV) in the brain early after intrarectal infection in rhesus monkeys, and that less than 0.2% of intravenously infused PGT121 enters the CSF, which is below the threshold for efficacy. We posit that re-engineering PGT121 as a bispecific antibody (PGT121/anti-HTfR Ab) to efficiently across the BBB will treat HAND by reducing viral load without the cART-associated toxicity. We will test this hypothesis by pursuing three specific aims: 1.) Re-engineer mAb PGT121 as a bispecific Ab for improved CNS penetration. 2.) Determine preliminary efficacy and safety of bispecific PGT121/anti-HTfR Ab in SHIV-infected rhesus monkeys. 3.) Reduce SHIV replication in CNS reservoirs of infected rhesus monkeys with bispecific PGT121/anti- HTfR Ab. To achieve these, the Tan lab will continue our ongoing collaboration with the Reimann lab in generating and testing the bispecific antibody PGT121/anti-HTfR Ab in Aim 1. The non-human primate studies in Aims 2 and 3 were developed and will be carried out in collaboration between the Tan and Barouch labs. The development of novel tools such as the bispecific antibody will pave the way for the discovery of new therapeutics for eradication of HIV from the CNS. This proposed work will expand our understanding of antibody-mediated responses within the CNS, and create new therapeutic interventions targeting HIV in the CNS.