Targeting HIV cell-to-cell transmission

描述（由申请人提供）：已知艾滋病毒从感染细胞传播到未感染细胞比无细胞病毒感染更有效。在体外，细胞-细胞接触刺激HIV复制100-10,000倍。艾滋病毒利用和操纵细胞间接触以实现有效传播的能力，对感染在全身的传播和艾滋病的进展起着至关重要的作用。细胞相关的艾滋病毒也被认为在性传播和母婴传播中起着重要作用。尽管它很重要，但人们对控制接触依赖性细胞间扩散的分子机制知之甚少，也没有针对这一步骤的抗病毒治疗。在这里，我们提出了一种团队科学方法来开发抗病毒疗法，专门防止HIV细胞间传播。我们将利用第一个强大的细胞间传播试验，可以定量测量病毒在细胞间的传播。我们将应用该试验分离接触依赖性细胞间传播所需的宿主因子。我们的综合方法将为科学界提供新的候选基因，这些基因有可能改变预防艾滋病毒传播的研究。然后，我们将使用人源化的HIV感染小鼠模型来直接测试我们确定的主要候选基因是否需要在粘膜递送后在体内建立HIV感染。最后，一个平行和互补的方法，我们将确定小分子的功能作为新的治疗特异性干扰艾滋病毒的传播。我们的基因和化学结合的方法将允许开发新的预防疗法，减少艾滋病的传播。这项研究计划将开发针对HIV在细胞间有效传播能力的抗病毒疗法。它将首先专注于基础科学，通过鉴定HIV传播所需的宿主基因，测试它们在体内的生理相关性，并启动一种翻译方法来分离特异性干扰HIV传播的小分子抑制剂。

DESCRIPTION (provided by applicant): HIV transmission from infected to uninfected cells is known to be more efficient than infection with cell-free virus. In vitro, cell-cell contact stimulates HIV replication 100-10,000 fold. The ability of HIV to utilize and manipulate cell-cell contact for the purpose of efficient transmission critically contributes to the spreading of infection throughout the body and the progression to AIDS. Cell-associated HIV is also thought to play an important role during sexual as well as mother to child transmissions. Despite its importance, very little is known about the molecular mechanisms that govern contact-dependent cell to cell spread and no antiviral therapy has been directed against this step. Here we propose a team science approach to develop antiviral therapies that specifically prevent HIV cell-to-cell transmission. We will take advantage of the first robust cell-to-cell transmission assay allowing the quantitative measurement of virus spreading from cell to cell. We will apply this assay to isolate host factors required for contact-dependent cell-to-cell transmission. Our comprehensive approach will provide the scientific community with novel candidate genes that have the potential to transform research on the prevention of HIV transmission. We will then use the humanized mouse model for HIV infection to directly test if our identified lead candidate genes are required for the establishment of HIV infection in vivo following mucosal delivery. Finally, a parallel and complementary approach we will identify small molecules that function as novel therapeutics specifically interfering with HIV transmission. Our combined genetic and chemical approach will allow the development of novel preventive therapies that reduce the spreading of AIDS. This research proposal will develop antiviral therapies that target the ability of HIV to efficiently spread from cell to cell. It will first focus on basic science by identifying host genes required for HIV transmission, test their physiological relevance in vivo and initiate a translational approach to isolate small molecule inhibitors that specifically interfere with HIV transmission.