Monocytes In Aids As Targets For Antiviral Therapy

该项目的研究旨在了解艾滋病毒-1感染的机制，特别是巨噬细胞的感染机制，并制定有效的战略来预防和/或抑制感染。免疫缺陷是HIV-1感染的后果，使宿主容易受到机会性感染。机会性感染反过来影响靶细胞对HIV-1感染和复制的易感性。以禽型支原体为模型共病原体，我们定义了多种病毒允许因子。此外，扁桃体和非感染性粘膜炎性病变中的免疫激活AS也可能与病毒复制的近端部位有关。激活/炎症和HIV-1感染增强之间的这些联系需要进一步阐明促进对HIV-1的易感性的因素。扁桃体代表了一个独特的微环境，拥有大量激活的和高度敏感的艾滋病毒目标。通过分离和培养携带艾滋病毒的扁桃体细胞，可以建立与敏感度较低的外周血单核细胞相比，增强易感性的表型、功能和分子相关性，并提供对干预靶点的洞察。在这些研究的扩展中，黏附的人外周血单核细胞来源的巨噬细胞暴露于R5嗜性HIV以实现细胞表面相互作用，并监测巨噬细胞的信号转导、即刻早期基因的表达以及与病毒复制相关的基因。随着信号级联、基因转录和巨噬细胞特异性病毒动力学之间的联系被阐明，可能会出现干扰艾滋病毒复制和再感染的新策略。

Research in this project is directed at understanding the mechanisms of HIV-1 infection, particularly in macrophages, and in developing an effective strategy to prevent and/or inhibit infection. Immunodeficiency, the consequence of HIV-1 infection, predisposes the host to opportunistic infections. In turn, opportunistic infections influence target cell susceptibility to HIV-1 infection and replication.Using M. avium as a model co-pathogen, we have defined multiple viral permissive factors. Moreover, immune activation as occurs in tonsils and non-infectious mucosal inflammatory lesions may also be associated with proximal sites of viral replication. These connections between activation/inflammation and enhancement of HIV-1 infection warrant further elucidation of the factors promoting permissiveness to HIV-1. The tonsil represents an unique microenvironment possessing a large reservoir of activated and highly susceptible HIV targets. By isolating and culturing tonsil cells with HIV, phenotypic, functional and molecular correlates of enhanced susceptibility, as compared to less sensitive peripheral blood mononuclear cells, can be established and provide insight into interventional targets. In an extension of these studies, adherent human peripheral blood monocyte-derived macrophages were exposed to R5 tropic HIV to enable cell surace interactions, and the macrophages monitored for signal transduction, expression of immediate early genes, and genes associated with viral replication. As the association between signaling cascades, gene transcription and macrophage-specific viral dynamics is elucidated, new strategies to interfere with HIV replication and re-infection may emerge.