TARGETED TOXIN THERAPY IN MACAQUE MODEL FOR AIDS

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 现代HAART疗法可实现的深刻病毒抑制，加上长期治疗的局限性和担忧，重新引发了对从人体内根除艾滋病毒前景的认真考虑。我们提出了一种新的方法来根除艾滋病毒感染细胞，尽管HAART受到高度抑制，但这些细胞仍然存在。中心假设是，针对高效感染细胞表面表达的病毒包膜糖蛋白的靶向毒素治疗，将显著降低在HAART存在的情况下持续存在的病毒载量。其原理是基于这样一个事实，即HAART药物有效地抑制病毒复制，但不直接消除已经感染的细胞；靶向毒素直接杀死受感染的细胞。我们将这种方法称为HAART互补，以区别于积极推行的HAART强化策略，即在现有的抑制性HAART方案中添加额外的复制抑制剂。美国国立卫生研究院的E.Berger博士和I.Pastan博士设计了针对gp120的靶向毒素CD4-PE，并对其进行了表征。在细胞培养和小鼠模型中，CD4-PE有效地杀伤表达HIV或SIV包膜病毒的细胞，并与HAART药物具有高度的协同作用。我们建议使用加州大学戴维斯分校T.North博士和P.Luciw博士开发的RT-Shiv/猕猴治疗模型来测试CD4-PE补充高度抑制的HAART的能力。大量的临床级CD4-PE是可用的，并将提供必要的数量，这项研究将在加州国家灵长类动物研究中心进行。North Group开发的高灵敏度和定量分析方法将用于检测血浆病毒血症，以及尸检后淋巴结和各种相关组织中的病毒RNA和DNA。病毒反弹的显著延迟将是这种组合方法有效性的证据。有针对性的毒素杀灭被认为是HAART根除艾滋病毒的关键补充。拟议的研究还有望对艾滋病毒在HAART期间持续存在的机制(S)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.