TARGETED TOXIN THERAPY IN MACAQUE MODEL FOR AIDS

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 现代高效抗逆转录病毒疗法可实现的深度病毒抑制，加上长期治疗的局限性和担忧，重新唤起了对从体内根除艾滋病毒的前景的认真考虑。我们提出了一种新的方法来根除HIV感染的细胞，尽管高度抑制性HAART仍然存在。中心假设是针对在生产性感染细胞表面上表达的病毒Env糖蛋白的靶向毒素治疗将显著降低HAART存在下持续存在的病毒载量。其基本原理是基于HAART药物有效抑制病毒复制，但不直接消除已经感染的细胞;靶向毒素直接杀死感染的细胞。我们将这种方法称为HAART互补，以区别于积极追求的HAART强化策略，即在现有的抑制性HAART方案中加入额外的复制抑制剂。E医生伯杰和我。NIH的Pastan设计并表征了CD 4-PE，一种针对gp 120的靶向毒素。CD 4-PE有效地杀死表达HIV或SIV的Env的细胞，并且在细胞培养物和鼠模型中与HAART药物高度协同。我们建议使用T.北和P。露西在加州大学戴维斯分校。可获得大量临床级CD 4-PE，并将为本研究提供必要数量，本研究将在加州国家灵长类动物研究中心进行。North小组开发的高灵敏度和定量分析将用于测量血浆病毒血症，以及尸检后淋巴结和各种相关组织中的病毒RNA和DNA。显著延迟的病毒反弹将是这种组合方法有效性的证据。靶向毒素杀伤被认为是HAART根除HIV的关键补充。拟议的研究也有望对HAART期间HIV持续存在的机制产生新的见解。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The profound viral suppression achievable with modern-day HAART regimens, coupled with the limitations and concerns of prolonged treatment, have revitalized serious consideration of the prospect for eradicating HIV from the body. We propose a novel approach to eradicate the HIV infected cells that persist despite highly suppressive HAART. The central hypothesis is that targeted toxin therapy, directed against the viral Env glycoprotein expressed on the surface of productively infected cells, will significantly reduce virus load persisting in the presence of HAART. The rationale is based on the fact that HAART drugs potently suppress virus replication, but do not directly eliminate cells that are already infected; the targeted toxin directly kills infected cells. We refer to this approach as HAART complementation, to be distinguished from the actively pursued strategy of HAART intensification whereby an additional replication inhibitor is added to an existing suppressive HAART regiment. Drs. E. Berger and I. Pastan at NIH have designed and characterized CD4-PE, a targeted toxin directed to gp120. CD4-PE potently kills cells expressing Env of HIV or SIV, and is highly synergistic with HAART drugs both in cell culture and a murine model. We propose to test the ability of CD4-PE to complement highly suppressive HAART, using the RT-SHIV/macaque treatment model developed by Drs. T. North and P. Luciw at UC Davis. Large quantities of clincal grade CD4-PE are available, and the necessary amounts will be provided for this study, which will be conducted at the California National Primate Research Center. Highly sensitive and quantitative assays developed by the North group will be used to measure plasma viremia, as well as viral RNA and DNA in lymph nodes and various relevant tissues following necropsy. A significantly delayed virus rebound will be evidence for efficacy of this combination approach. Targeted toxin killing is proposed as a critical complement to HAART for HIV eradication. The proposed studies are also expected to yield novel insights into the mechanism(s) of HIV persistence during HAART.