Transmitted/Founder SHIV macaque model

描述(由申请人提供)：迄今为止，针对HIV-1的几项实质性疫苗努力都失败了，主要是因为到目前为止，我们还没有确定保护性免疫的相关性，以及能够在体内诱导这种保护性免疫反应的最佳疫苗配方。只有选定的单一或有限的病毒种类通过粘膜途径传播的知识促进了传递者/创立者病毒(T/F)的概念。有理由认为，这种优先传播的病毒应该成为艾滋病毒疫苗努力的目标。因此，构成世界性传播的主要分支的C分支病毒已成为疫苗配方研究的重点。然而，目前还缺乏合适的分支C病毒和最佳的非人类灵长类动物模型来忠实地模拟这种自然传播，以便将其用于候选疫苗或杀微生物剂的测试。本提案旨在为实现这些目标奠定初步基础。我们实验室有来自卢旺达-赞比亚正在进行的异性传播研究的具有复制能力的T/F病毒的独特的感染性分子克隆(IMC)对。我们的实验室在过去已经制备和测试了许多SHIV，因此在开发这些独特的T/F克隆病毒并在体外和体内制备具有复制能力的分支C T/F env-shiv方面经验丰富，它们将具有测试候选疫苗所需的所有特性。我们计划开展系统研究，包括1)使用一组测试来获得这种重组SHIV并对其进行详细的体外鉴定；2)利用我们实验室优化的新型体内细胞谱系耗竭技术，尝试使SHIV适应于在此类模型中的有效复制，从而分离出大量SHIV；以及3)测试具有体外和体内复制能力的SHIV群以进行粘膜传播。我们认为，在试剂、人才、经验和知识方面，我们有得天独厚的条件来实现本提案中概述的目标。

DESCRIPTION (provided by applicant): Several substantial vaccine efforts against HIV-1 have so far failed primarily because to date we have failed to identify the correlates of protectiv immunity and the optimal vaccine formulation that can induce such protective immune responses in vivo. The knowledge that only select single or limited virus species are transmitted via the mucosal route has advanced the concept of Transmitter/Founder viruses (T/F). It is reasoned that such viruses that are preferentially transmitted should be the target of HIV vaccine efforts. The clade 'C' viruses that constitute the major clade transmitted sexually worldwide therefore have become the focus of studies for vaccine formulations. However, there is a lack of both suitable clade 'C' viruses and an optimal nonhuman primate model that faithfully mimics such natural transmission so that it can be utilized for the testing of candidate vaccines or microbicides. The present proposal is directed at providing the initial foundation for these objectives. Our lab has available unique pairs of infectious molecular clones (IMC) of replication competent T/F viruses from heterosexual transmission studies being conducted in Rwanda-Zambia. Our lab has prepared and tested a number of SHIVs in the past and is thus highly experienced to exploit these unique sets of T/F cloned viruses and prepare in vitro and in vivo replication competent clade C T/F env-SHIVs which will share all the properties required for the testing of candidate vaccines. We plan to carry out systematic studies that include 1) the derivation and the detailed in vitro characterization of such recombinant SHIVs using a battery of tests 2) To utilize novel in vivo cell lineage depletion techniques that our lab has optimized i rhesus macaques and attempt to adapt the SHIVs for efficient replication in such models leading to the isolation of swarms of SHIVs stocks and 3) to test such in vitro and in vivo replication competent swarms of SHIV's for mucosal transmission. We submit that we are uniquely poised in terms of reagents, talent, experience and knowledge to achieve the objectives outlined in this proposal.