Role of 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。反过来，机会性感染影响目标细胞对HIV-1感染和复制的敏感性。以禽类支原体为模型共病原，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。在母乳喂养期间，粘膜表面也是艾滋病毒母婴传播的场所，努力确定传播的动力学以及影响病毒传播的先天性和获得性宿主防御机制的表达。在初乳中发现内源性抗病毒分子，包括分泌性白细胞蛋白酶抑制物(SLPI)和凝血酶反应蛋白(TSP-1)，它们对HIV-1感染有抑制作用，然后下降，提示可能存在加强防御的时间间隔。

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.