Role of 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，并制定有效的策略来预防和/或抑制感染。免疫缺陷，HIV-1感染的后果，使宿主容易受到机会性感染。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。以禽支原体为模型共病原体，我们定义了多种病毒容许因子。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部位有关。这些激活/炎症与HIV-1感染增强之间的联系，为进一步阐明促进HIV-1纵容性的因素提供了依据。扁桃体代表了一个独特的微环境，拥有大量激活和高度易感的HIV靶点。通过分离和培养带有HIV病毒的扁桃体细胞，与敏感性较低的外周血单个核细胞相比，可以建立增强易感性的表型、功能和分子相关关系，并为干预靶点提供见解。在母乳喂养期间，粘膜表面也是母婴HIV传播的一个场所，研究人员致力于确定传播动力学以及影响病毒传播的先天和获得性宿主防御机制的表达。内源性抗病毒分子，包括分泌性白细胞蛋白酶抑制剂（SLPI）和血小板反应蛋白（TSP-1），它们对HIV-1感染单核细胞有抑制作用，在初乳中发现，然后下降，提示增强防御的潜在间隔。

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. The mucosal surface is also a site of maternal-to-child HIV transmission during breastfeeding and efforts are directed at defining the kinetics of transmission and the expression of innate and acquired host defense mechanisms which impact on viral transmission. Endogenous antiviral molecules, including secretory leukocyte protease inhibitor (SLPI) and thrombospondin (TSP-1), which have inhibitory actions on HIV-1 infection of mononuclear cells, are found in colostrum and then decline suggesting a potential interval of enhanced defense.