Modulation of innate immunity by HIV-1 gene products

描述(申请人提供)：与HIV-1感染相关的免疫发病机制的特征是免疫系统细胞群体的几种功能异常以及CD4+T淋巴细胞的数量和功能的进行性下降。尽管作出了许多努力，但最终导致艾滋病发展的机制尚未完全阐明。这项建议的总体目标是描述早期HIV的相互作用以及HIV-1基因产物对先天免疫系统细胞群体的旁观者效应，目的是确定与病毒持续和免疫系统功能障碍有关的新机制，以了解艾滋病的免疫发病机制。基于免疫反应的功能结果很可能由所引发的天然免疫反应的类型决定的工作假设，该项目预计将实现以下目标： I)确定艾滋病毒早期与巨噬细胞和DC相互作用对Toll样受体表达/激活的影响 二)确定早期艾滋病毒/靶细胞相互作用触发的分子信号及其在艾滋病毒介导的功能细胞改变中的作用 Iii)表征HIV-1VPR辅助蛋白对连接先天和获得性反应的效应细胞的免疫调节活性。 预计这项研究可以为免疫病理机制的重要方面提供新的解释基础，这可能对最终开发有效的预防和治疗干预措施至关重要。

DESCRIPTION (provided by applicant): The immunopathogenesis associated with HIV-1 infection is characterized by several functional abnormalities of immune system cell populations and by a progressive decline in the numbers and functions of CD4+ T lymphocytes. In spite of many efforts, the mechanisms ultimately leading to the development of AIDS have not yet been fully elucidated. The general goal of this proposal is to characterize early HIV interactions as well as bystander effects of HIV-1 gene products on cell populations of the innate immunity system to the aim of defining novel mechanisms involved in viral persistence and immune system dysfunctions relevant to the comprehension of immunopathogenesis of AIDS. Based on the working hypothesis that the functional outcome of the immune response is likely to be determined by the type of innate immune response elicited, the project foresees the following objectives: i) Determine the effects of early HIV interaction with macrophages and DCs on the expression/activation of Toll-like receptors ii) Define the molecular signals triggered by early HIV/target cell interactions and their role in HIV mediated functional cell alterations iii) Characterize the immunomodulatory activities of HIV-1 Vpr accessory protein on effector cells linking innate and adaptive responses. It is expected that this research could provide the basis for a novel interpretation of important aspects of immunopathogenesis which may be critical to the ultimate development of effective prophylactic and therapeutic interventions.