Mechanism of cell-associated HIV-1 transmission

描述(申请人提供)：人类免疫缺陷1型(HIV-1)在人类中的性传播的特征是该病毒具有跨越粘膜上皮屏障并启动对底层组织细胞的感染的显著能力。存在于外周粘膜组织中的未成熟树突状细胞亚群捕获病毒颗粒，迁移到外周淋巴结，成熟并通过与T细胞相互作用帮助启动针对入侵病原体的适应性免疫反应。反过来，艾滋病毒利用树突状细胞和T细胞的相互作用在感染者中传播。虽然HIV颗粒可以被树突状细胞特异性附着因子如树突状细胞特异性细胞间黏附分子抓取非整合素(DC-SIGN)捕获，但这些捕获的颗粒如何转移到CD4T细胞仍不清楚。我们建议研究树突状细胞介导的HIV-1向T细胞传播的机制。我们将探索这样的假设：捕获的病毒颗粒进入独特的细胞内隔间，在那里HIV保持不丧失传染性，并且在正常的树突状细胞-T细胞相互作用过程中，病毒颗粒被释放，以促进T细胞的强大感染。细胞相关病毒转移的机制将通过以下具体目标加以解决： 1)确定捕获后含有感染性病毒颗粒的树突状细胞内隔室的性质；2)探索HIV如何进入这个细胞内隔室，特别是在DCSIGN结合之后，以及病毒颗粒与DC-SIGN结合所针对的内吞途径的性质是否定义了HIV在树突状细胞中的长期传染性；3)确定刺激内化的HIV释放到细胞外环境的信号。我们相信，在这些目标中描述的研究将描绘树突状细胞，特别是DC-SIGN，在体内HIV-1感染的启动和传播中的作用。

DESCRIPTION (provided by applicant): Sexual transmission of human immunodeficiency type 1 (HIV-1) in humans is characterized by the remarkable ability of the virus to transverse mucosal epithelial barriers and initiate infection of cells in the underlying tissues. Immature dendritic cell subsets present in the peripheral mucosal tissues capture virus particles, migrate to peripheral lymph nodes, mature and help initiate adaptive immune responses against the invading pathogen by interacting with T cells. HIV, in turn, has exploited dendritic cell - T cell interactions for its dissemination in the infected individual. Though HIV particles can be captured by dendritic cell-specific attachment factors such as dendritic cell-specific intercellular adhesion molecule grabbing non-integrin (DC-SIGN), it remains unclear as to how these captured particles are transferred to CD4+ T cells. We propose herein to study the mechanism of dendritic cell mediated HIV-1 transmission to T cells. We will explore the hypothesis that captured virus particles traffic to unique intracellular compartments where HIV is maintained without loss of infectivity, and that during the course of normal dendritic cell - T cell interactions virus particles are released to facilitate robust infections of T cells. The mechanism of cell associated virus transfer will be addressed by the following Specific Aims: 1) To define the nature of intracellular compartment in dendritic cells that harbors infectious virus particles following capture; 2) To explore how HIV accesses this intracellular compartment, specifically following DCSIGN binding and whether the nature of the endocytic pathway that is targeted by virus particle binding to DC-SIGN defines long term infectivity of HIV in dendritic cells; 3) To determine the signals that stimulate the release of internalized HIV to the extracellular milieu. We believe that the studies described in these aims would delineate the role of dendritic cells, and especially DC-SIGN, in the initiation and propagation of HIV-1 infection in vivo.