Monocytes In Aids And 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。将贴壁的人外周血单核细胞来源的巨噬细胞暴露于R5嗜性HIV以实现细胞表面的相互作用，并通过基因芯片分析监测巨噬细胞的信号转导、即刻早期基因和与病毒复制相关的下游基因的表达。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。在这一点上，在HIV-1感染的巨噬细胞中持续上调的基因之一是分化标志CDKN1A，调节这种激酶抑制物在体外对病毒感染和复制有影响，可能是治疗的重要靶点。

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. Adherent human peripheral blood monocyte-derived macrophages were exposed to R5 tropic HIV to enable cell surface interactions, and the macrophages monitored for signal transduction, expression of immediate early genes, and downstream genes associated with viral replication by cDNA microarray analyses. 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. In this regard, one of the genes consistently upregulated in HIV-1 infected macrophages was a differentiation marker, CDKN1A, and regulation of this kinase inhibitor has an impact on viral infection and replication in vitro and may be an important target in therapy.