ASSESSMENT OF AFE INHIBITORS IN DC-T CELL MIXTURES

DC-T 细胞混合物中 AFE 抑制剂的评估

• 批准号: 6955351
• 负责人: Melissa J Robbiani
• 金额: $ 25.08万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6955351
• 关键词: AIDS education /prevention; HIV infections; Macaca mulatta; T lymphocyte; antiAIDS agent; cell cell interaction; chemoprevention; dendritic cells; drug screening /evaluation; human tissue; microorganism interaction; mucosa; virus infection mechanism; virus replication; virus virus interaction

Dendritic cells (DCs) and T cells are among the first leukocytes targeted by HIV after mucosal exposure and DCs promote virus replication in concert with CD4+ T cells. Different subsets of DCs and T cells, and the type of virus influence the level of virus growth in the DC-T cell milieu. DCs express CD4, chernokine receptors (CCRs), and mannose-dependent C-type lectin receptors (MCLRs) that are used by the virus for binding and entry. With such diversity, DCs promote virus amplification in two ways; replicating virus themselves and transmitting this to permissive CD4+ T cells (immature DCs) or directly transferring entrapped virions to CD4+ T cells in the absence of DC infection (immature and mature DCs). Directly interfering with specific DC-virus interactions and transmission of virus between cells represents a promising anti-viral strategy that is of relevance to the development of mechanism-based microbicides. This project will focus on defining how putative attachment, fusion, and entry (AFE) inhibitory that target virus envelope interactions with CD4, MCLRs, or CCRs impact DC-virus interplay and their ability to drive virus spread between cells in vitro, and whether the presence of common co-pathogens like HSV-2 or Candida albicans impact the efficacy of the AFE inhibitors. The questions being considered are: 1 - Which AFE inhibitors block binding, uptake, or spread of virus by DCs in the DC-T cell milieu without interfering with normal DC biology? 2 - Are AFE inhibitors able to impede virus dissemination to antigen-specific T cells? 3 - Do mucosal co-pathogens impact how AFE inhibitors block HIV capture and spread by DCs? These studies will reveal critical details about how agents that prevent virus fusion and entry block DC-driven virus spread, a central event in establishing mucosal infection. Identifying effective strategies to impede DC-virus interplay without impairing DC function even in the face of co-pathogens is vital to advance the microbicide field.

树突状细胞 (DC) 和 T 细胞是粘膜暴露后最先被 HIV 靶向的白细胞之一，DC 与 CD4+ T 细胞协同促进病毒复制。 DC 和 T 细胞的不同亚群以及病毒类型会影响 DC-T 细胞环境中病毒的生长水平。 DC 表达 CD4、切尔诺因子受体 (CCR) 和甘露糖依赖性 C 型凝集素受体 (MCLR)，病毒利用这些受体进行结合和进入。凭借这种多样性，树突状细胞以两种方式促进病毒扩增：复制病毒本身并将其传递给允许的 CD4+ T 细胞（未成熟​​的 DC），或者在没有 DC 感染的情况下（未成熟和成熟的 DC）直接将捕获的病毒颗粒传递给 CD4+ T 细胞。直接干扰特定的 DC 病毒相互作用和病毒在细胞之间的传播代表了一种有前途的方法 与基于机制的杀微生物剂的开发相关的抗病毒策略。 该项目将重点定义针对病毒包膜与 CD4、MCLR 或 CCR 相互作用的推定附着、融合和进入 (AFE) 抑制如何影响 DC 病毒相互作用及其在体外驱动病毒在细胞之间传播的能力，以及是否HSV-2 或白色念珠菌等常见共病原体的存在会影响 AFE 抑制剂的功效。 正在考虑的问题是： 1 - 哪些 AFE 抑制剂可以阻止 DC-T 细胞环境中 DC 结合、摄取或传播病毒，而不干扰正常的 DC 生物学？ 2 - AFE 抑制剂是否能够阻止病毒传播至抗原特异性 T 细胞？ 3 - 粘膜共病原体是否会影响 AFE 抑制剂阻止 DC 捕获和传播 HIV 的方式？这些研究将揭示有关防止病毒融合和进入的药物如何阻止 DC 驱动的关键细节 病毒传播是建立粘膜感染的核心事件。确定有效的策略来阻止 DC 病毒相互作用，即使面对共同病原体，也不损害 DC 功能，这对于推进杀菌剂领域至关重要。