BLOCKING VIRUS SPREAD BY DCS WITH CARRAGEENAN-BASED COMPOUNDS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。导致HIV跨粘膜感染的早期事件可能涉及上皮细胞和白细胞表面的各种分子捕获HIV，然后感染组织内的允许靶细胞。在这一生物学研究中，我们主要关注树突状细胞（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。早期的研究证实，DC驱动的病毒向T细胞传播至少有两个阶段：一个阶段涉及被DC捕获（但未感染）的病毒直接传递给T细胞，另一个阶段涉及DC感染和新合成病毒的传播。被树突细胞捕获的病毒通过树突细胞和T细胞之间自然形成的突触迅速传播到CD4 T细胞。融合抑制剂T1249的加入减少了病毒向T细胞移动的数量，同时增加了dc中积聚的病毒数量。其免疫学和病毒学后果正在调查中。这些数据强调，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，以测试更广泛作用的卡拉胶基配方的能力，以检测它们是否有能力阻止促进传播所需的复杂病毒-细胞相互作用。卡拉胶基杀菌剂具有广泛的抗HIV/SIV和其他性传播病原体的活性，因此前景广阔。卡拉胶破坏体外dc对病毒的捕获，并阻断允许DC-T细胞混合物的感染。最近的体内实验数据显示，卡拉胶基杀菌剂可以保护猕猴免受阴道SHIV的攻击。这些数据鼓舞了未来以卡拉胶为基础的配方在预防艾滋病毒传播方面的应用。

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.