Attachment and fusion inhibitors potently prevent dendritic cell-driven HIV infection.
Attachment and fusion inhibitors potently prevent dendritic cell-driven HIV infection.
复制标题
附着和融合抑制剂有效防止树突状细胞驱动的HIV感染。
DOI：
10.1097/qai.0b013e3181ff2aa5
复制
发表时间：
2011-03-01
期刊：
影响因子：
--
通讯作者：
Robbiani M
中科院分区：
文献类型：
--
作者：
Frank I;Robbiani M
树突状细胞（DC）有效地将捕获的（反式）或从头产生的（顺式）病毒转移到CD 4 T细胞。使用单核细胞衍生的DC，我们评估了靶向HIV包膜（BMS-C，T-1249）或CCR 5（CMPD 167）的进入抑制剂预防DC感染、DC驱动的反式和顺式T细胞感染以及DC-T细胞混合物直接感染的效力。与匹配的成熟DC-T培养物或感染的未成熟DC相比，具有不同病毒转移机制的未成熟DC-T培养物产生相似的感染水平，并产生更多的前病毒DNA。尽管所有化合物都完全阻断了HIV复制，但与生产性DC-T细胞共培养物相比，需要16倍以上的每种抑制剂（250对15.6nM）来防止DC的低水平感染。在所有测试的细胞系统中，BMS-C最有效地阻断了感染。BMS-C在预防DC感染方面比CMPD 167显著更有效。事实上，低剂量的CMPD 167显著增强DC感染。当用CMPD 167培养未成熟DC时，观察到升高的CCL 4水平。病毒进入抑制剂不干扰白念珠菌特异性DC细胞因子/趋化因子反应。这些研究结果表明，一种与病毒结合的小分子是一种很有前途的工具，用于局部杀微生物剂的设计，以防止感染的早期目标需要建立和传播艾滋病毒感染。
Dendritic cells (DCs) efficiently transfer captured (trans) or de novo produced (cis) virus to CD4 T cells. Using monocyte-derived DCs we evaluated entry inhibitors targeting HIV envelope (BMS-C, T-1249) or CCR5 (CMPD167) for their potency to prevent DC-infection, DC-driven infection in T cells in trans and cis, and direct infection of DC-T cell mixtures. Immature DC-T cultures with distinct mechanisms of viral transfer yielded similar levels of infection, and produced more proviral DNA compared to matched mature DC-T cultures or infected immature DCs. Although all compounds completely blocked HIV replication, 16 times more of each inhibitor (250 vs 15.6nM) was required to prevent low-level infection of DCs compared to the productive DC-T cell cocultures. Across all cell systems tested, BMS-C blocked infection most potently. BMS-C was significantly more effective than CMPD167 at preventing DC infection. In fact, low doses of CMPD167 significantly enhanced DC-infection. Elevated levels of CCL4 were observed when immature DCs were cultured with CMPD167. Viral entry inhibitors did not interfere with Candida albicans-specific DC cytokine/chemokine responses. These findings indicate that an envelope-binding small molecule is a promising tool for topical microbicide design to prevent the infection of early targets needed to establish and disseminate HIV infection.