BLOCKING VIRUS SPREAD BY DCS WITH CARRAGEENAN-BASED COMPOUNDS

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。导致HIV跨粘膜感染的早期事件可能涉及HIV被上皮细胞和白细胞表面上的多种分子捕获，随后感染组织内的容许靶细胞。在研究这种生物学时，我们专注于树突状细胞（DC）和T细胞对这些事件的贡献，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，DC驱动的病毒向T细胞的传播至少有两个阶段：一个涉及直接交给T细胞的DC捕获的病毒（但不感染），另一个涉及DC感染和新合成病毒的传播。由DC捕获的病毒被传递到CD 4 T细胞，其快速穿过DC和T细胞之间天然产生的突触。融合抑制剂T1249的包含减少了病毒移动到T细胞的量，同时增加了DC中积累的病毒的量。其免疫学和病毒学后果正在调查中。这些数据强调了仅阻断病毒-DC相互作用的某些途径在预防DC驱动的HIV传播方面是次优的。因此，正在进行更多的研究，以测试更广泛的作用角叉菜胶为基础的配方的能力，以阻止复杂的病毒-细胞相互作用，以促进传播的能力。基于卡拉胶的杀微生物剂由于其对HIV/SIV和其他性传播病原体的广泛活性而很有前途。卡拉胶在体外削弱DC的病毒捕获并阻断允许的DC-T细胞混合物的感染。最近在体内的数据显示，猕猴保护阴道SHIV的挑战，角叉菜胶为基础的杀微生物剂。这些数据对于将来应用基于角叉菜胶的制剂预防HIV传播是令人鼓舞的。

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 T1249 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.