Cell Biology of Retrovirus Replication

描述（由申请人提供）：具体而言，我们提出了一个竞争性修订申请，我们的积极授权2 R 01 CA 098727“逆转录病毒复制的细胞生物学”。逆转录病毒为了传播的目的而有效操纵细胞-细胞接触的能力对逆转录病毒诱导的疾病如白血病和AIDS的进展有重要贡献。我们的授权2 R 01 CA 098727致力于确定逆转录病毒建立和操纵细胞-细胞接触的机制，以便在细胞之间有效传播。在这里，我们提出了一个有竞争力的修订申请，以建立直接可视化所需的实验条件，第一次，逆转录病毒在体内传播使用活体双光子显微镜。由于两项重要的技术突破，拟议的方法是可以实现的。首先，我们已经确定了艾滋病毒的变种作为第一个荧光标记的逆转录病毒，可以看到双光子显微镜。第二，新的人源化小鼠模型提供了一种可用于活体成像的HIV感染的小动物模型。这两项进展使我们能够开发技术，允许使用HIV感染的人源化小鼠模型可视化HIV在体内的传播。我们的资助将克服与体外研究相关的限制，并有可能彻底改变我们对逆转录病毒在活生物体中传播的理解。 公共卫生相关性：主动授权2 R 01 CA 098727的竞争性修订申请是对NOT-OD-09-058的回应，并提出建立首次使用活体双光子显微镜直接观察体内逆转录病毒传播所需的实验条件。该提案将克服与体外研究有关的限制，并将大大提高主动赠款的质量、范围和相关性。

DESCRIPTION (provided by applicant): Specifically, we propose a Competitive Revision Application for our active grant 2R01CA098727 "Cell Biology of Retrovirus Replication". The ability of retroviruses to efficiently manipulate cell-cell contacts for the purpose of spreading critically contributes to the progression to retrovirally induced diseases such as leukemia and AIDS. Our grant 2R01CA098727 is devoted to the determination of the mechanism by which retroviruses establish and manipulate cell-cell contact for the purpose of efficient spreading from cell to cell. Here we propose a Competitive Revision Application to establish the experimentally conditions needed to directly visualize, for the first time, retroviral spreading in vivo using intravital two-photon microscopy. The proposed approach is within reach due to two important technical breakthroughs. First, we have identified an HIV variant as the first fluorescently labeled retrovirus that can be seen by two-photon microscopy. Second, new humanized mouse models provide a small animal model for HIV infection that is accessible to intravital imaging. Both advances allow us to develop the technologies that permit the visualization of HIV spreading in vivo using the humanized mouse model of HIV infection. Our grant will overcome the limitation associated with in vitro studies and has the potential to revolutionize our understanding of retroviral spreading as it happens in living organism. PUBLIC HEALTH RELEVANCE: This Competitive Revision Application for the active grant 2R01CA098727 is in response to NOT-OD-09-058 and proposes the establishment of the experimentally conditions needed to directly visualize, for the first time, retroviral spreading in vivo using intravital two-photon microscopy. The proposal will overcome the limitation associated with in vitro studies and will significantly elevate the quality, scope and relevance of the active grant.