Antibody-based eradication of HIV from the CNS reservoirs

尽管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 在他们的大脑中携带艾滋病毒，并有患艾滋病毒相关神经认知障碍（HAND）的风险。这部分是 由于cART的CNS渗透不完全。然而，cART对脑组织的毒性也与 用手。因此，需要新的治疗方法来治疗CNS中的HIV而不引起毒性。近日一 一种新的广泛中和的抗HIV单克隆抗体（mAb），PGT 121，被证明可以控制 病毒复制在猿猴人类免疫缺陷病毒（SHIV）感染的恒河猴的血液中。 然而，只有有限量的PGT 121穿透血脑屏障（BBB）;并且PGT 121也不能穿透血脑屏障。 已知PGT 121是否在CNS环境中保留其功能。我们的总体目标是减少 CSN通过重新设计PGT 121以更好地穿透BBB。我们将创造一种双特异性抗体， PGT 121是抗体的一个臂，另一个臂结合BBB上的人转铁蛋白受体（HTfR 以促进主动转胞吞作用（PGT 121/抗HTfR Ab）。中心假设是静脉输注 PGT 121/抗HTfR Ab将特异性靶向CNS中的HIV。我们的初步数据显示， IgG谱，猴免疫缺陷病毒（SIV）在直肠内感染后早期脑中的检测， 恒河猴，并且少于0.2%的静脉输注的PGT 121进入CSF，这低于 功效阈值。我们证实，将PGT 121重新工程改造为双特异性抗体（PGT 121/抗HTfR Ab）， 有效地穿过BBB将通过降低病毒载量而没有cART相关毒性来治疗HAND。我们将 通过追求三个具体目标来检验这一假设： 1.）的人。将mAb PGT 121重新设计为双特异性抗体，以改善CNS渗透。 2.）确定双特异性PGT 121/抗HTfR Ab在SHIV感染者中的初步疗效和安全性 恒河猴 3.）第三章用双特异性PGT 121/抗-GST 121抗体降低感染恒河猴CNS储库中的SHIV复制 HTfR抗体 为了实现这些目标，Tan实验室将继续与Reimann实验室合作， 测试目标1中的双特异性抗体PGT 121/抗HTfR Ab。目的2和3中的非人灵长类动物研究 将在Tan和Barouch实验室之间合作开发并实施。发展 新的工具，如双特异性抗体，将为发现新的治疗方法铺平道路。 从CNS中根除HIV。 这项拟议的工作将扩大我们对CNS内抗体介导的反应的理解， 针对CNS中HIV的新治疗干预。

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.