BLOCKING VIRUS SPREAD BY DCS WITH CARRAGEENAN-BASED COMPOUNDS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 导致整个粘膜的艾滋病毒感染的早期事件可能涉及到艾滋病毒被上皮细胞和白细胞表面的各种分子捕获，然后感染组织内的允许靶细胞。在研究这一生物学过程中，我们重点关注树突状细胞(DC)和T细胞在这些事件中的作用，并探索在体外和体内阻断这些复杂事件的有效方法。早期的工作证实，至少存在两个阶段的DC驱动的病毒向T细胞的传播，一个阶段是由DC捕获(但不感染)的病毒直接传递给T细胞，另一个阶段是DC感染和新合成的病毒的传播。由DC捕获的病毒被传播到CD4T细胞，通过DC和T细胞之间自然产生的突触快速移动。融合抑制剂的加入减少了病毒向T细胞的移动，同时增加了树突状细胞中积累的病毒数量。其免疫学和病毒学后果正在调查中。这些数据突显出，在防止DC驱动的艾滋病毒传播方面，仅阻止病毒-DC相互作用的某些途径是次优的。因此，正在进行更多的研究，以测试更广泛的作用卡拉胶制剂的能力，以确定它们是否有能力阻止促进传播所需的复杂的病毒-细胞相互作用。基于卡拉胶的杀微生物剂前景看好，因为它们对艾滋病毒/SIV和其他性传播病原体具有广泛的活性。角叉菜胶能在体外损害DC对病毒的捕获，并阻断允许的DC-T细胞混合物的感染。最近的活体数据显示，以卡拉胶为基础的杀菌剂可以保护猕猴免受阴道SIV病毒的攻击。这些数据对于以卡拉胶为基础的制剂在预防艾滋病毒传播方面的应用是令人鼓舞的。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Early events leading to HIV infection across the mucosa likely involve HIV capture by a wide variety of molecules on the surface of epithelial cells and leukocytes followed by infection of permissive target cells within the tissues. In studying this biology, we are focusing on the contribution of dendritic cells (DCs) and T cells to these events and exploring effective ways to block these complex events in vitro and in vivo. Earlier work confirmed that there are at least two phases of DC-driven transmission of virus to T cells  one involves virus captured by (but not infecting) DCs that is handed directly over to the T cells and the other involves DC infection and the transmission of newly synthesized viruses. Virus captured by DCs is transmitted to CD4 T cells moving rapidly across the synapse naturally created between DCs and T cells. Inclusion of the fusion inhibitor reduces the amount of virus movement to the T cells, while increasing the amount of virus accumulating in the DCs. The immunologic and virologic consequences of this are under investigation. These data highlight how only blocking certain pathways of virus-DC interactions are suboptimal in preventing DC-driven HIV spread. As a result, additional studies are being performed to test the ability of more broad acting carrageenan-based formulations for their ability to impede the complex virus-cell interplay needed to facilitate transmission. Carrageenan-based microbicides are promising due to their wide rage of activity against HIV/SIV and other sexually transmitted pathogens. Carrageenans impair virus capture by DCs in vitro and block infection of permissive DC-T cell mixtures. Recent in vivo data revealed that macaques were protected against vaginal SHIV challenge by carrageenan-based microbicides. These data are encouraging for future application of carrageenan-based formulations in preventing HIV spread.