Transmitted/Founder SHIV macaque model

 描述（由申请人提供）：迄今为止，针对HIV-1的几种实质性疫苗努力都失败了，主要是因为迄今为止，我们未能鉴定保护性免疫的相关性和能够在体内诱导这种保护性免疫应答的最佳疫苗制剂。只有选择的单一或有限的病毒物种通过粘膜途径传播的知识已经推进了传播者/创始人病毒（T/F）的概念。有理由认为，这些优先传播的病毒应该成为艾滋病毒疫苗工作的目标。因此，构成全世界性传播的主要进化枝的进化枝"C"病毒已成为疫苗制剂研究的焦点。然而，缺乏合适的进化枝"C"病毒和最佳的非人灵长类动物模型，该模型忠实地模拟这种自然传播，使得它可以用于测试候选的病毒。 疫苗或杀菌剂。本建议旨在为这些目标奠定初步基础。我们的实验室有独特的传染性分子克隆（IMC）的复制能力T/F病毒的异性传播研究正在卢旺达-赞比亚进行。我们的实验室在过去已经制备和测试了许多SHIV，因此在利用这些独特的T/F克隆病毒集和制备体外和体内复制能力的进化枝C T/F env-SHIV方面经验丰富，这些进化枝C T/F env-SHIV将具有测试候选疫苗所需的所有特性。我们计划进行系统的研究，包括1）使用一系列测试对这种重组SHIV进行衍生和详细的体外表征2）为了利用我们实验室已经优化的恒河猴体内细胞谱系耗竭新技术，并尝试使SHIV适应在这种模型中的有效复制，从而导致SHIV群的分离，以及3）以测试这种体外和体内复制能力的SHIV群的粘膜传播。我们认为，我们在试剂、人才、经验和知识方面具有独特的优势，可以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 are 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.