Monocytes In Aids And As Targets For Antiviral Therapy

该项目的研究旨在了解HIV-1感染的机制，特别是在巨噬细胞中，并制定有效的预防和/或抑制感染的策略。HIV-1感染的后果是免疫缺陷，使宿主易于机会性感染。反过来，机会性感染影响靶细胞对HIV-1感染和复制的易感性。禽流感作为模式共病原体，我们定义了多种病毒允许因素。此外，扁桃体和非感染性粘膜炎性病变中发生的免疫激活也可能与病毒复制的近端位点相关。这些激活/炎症和增强HIV-1感染之间的联系保证了进一步阐明促进对HIV-1的宽容的因素。粘附的人外周血单核细胞衍生的巨噬细胞暴露于R5嗜性HIV以使细胞表面相互作用，并通过cDNA微阵列分析监测巨噬细胞的信号转导、立即早期基因的表达和与病毒复制相关的下游基因。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关联被阐明，可能出现干扰HIV复制和再感染的新策略。在这方面，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物CDKN 1A，这种激酶抑制剂的调节对体外病毒感染和复制有影响，可能是治疗中的重要靶点。

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.