Systems biology analysis of in vivo impact of substance abuse on HIV infection

描述（由申请方提供）：性接触后，HIV穿过粘膜屏障，建立感染细胞的病灶，这些细胞扩增初始感染接种物，并通过淋巴和血管系统启动随后的全身传播。一些证据表明，长期接触滥用药物与艾滋病毒感染的风险增加和进展加快有关。大量感染艾滋病毒的人是娱乐性毒品使用者，在传播感染方面起着主要作用，必须通过任何拟议的方案进行有效治疗，以减少艾滋病毒感染的传播。通过阐明药物增加艾滋病毒传播风险的机制以及药物滥用对治疗效果的影响，可能会加强对这一人群的有效治疗设计。我们假设暴露于滥用药物，如阿片类药物或安非他明，通过改变淋巴微环境，促进淋巴组织中HIV的感染和复制，导致物质滥用者HIV感染率增加。阻碍调查的主要障碍 HIV感染的早期事件，特别是药物滥用的影响，是缺乏可被HIV感染的动物模型。最近，已经使用移植有人造血干细胞的高度免疫缺陷小鼠开发了更稳健的人源化小鼠模型，例如hu-NSG小鼠。这些小鼠表现出小鼠淋巴组织与人T细胞、B细胞、巨噬细胞和树突细胞的广泛移植，使它们能够通过静脉内、腹膜内、直肠或阴道途径感染HIV。我们建议结合联合收割机这种新的体内实验模型，研究艾滋病毒传播的系统生物学方法，分析和表征药物滥用对艾滋病毒感染的初始和随后的细胞靶点的影响，在建立艾滋病毒感染，并产生微阵列数据集，以确定阿片类药物或甲基的使用，有助于他们的启动和传播的增强调制的基因。这项拟议研究的结果将提供对人源化小鼠中HIV感染的多尺度理解，使用专用实验和建模的系统生物学分析，这将使我们能够对HIV感染如何在淋巴组织中启动和传播以及如何受到药物滥用的影响进行机械和定量的把握。

DESCRIPTION (provided by applicant): After sexual exposure HIV crosses the mucosal barrier, establishes a nidus of infected cells which amplify the initial infectious inoculum and initiates subsequent systemic dissemination through the lymphatic and vascular systems. Several lines of evidence have indicated that chronic exposure to drugs of abuse is associated with an increased risk for the acquisition and faster progression of HIV infection. The large cohort of HIV-infected individuals who are recreational drug users and play a major role in disseminating infection must be effectively treated by any proposed regimen to reduce the spread of HIV infection. Design of effective treatments for this population would likely be enhanced by delineating the mechanisms by which substance increases the risk of HIV transmission and the impact of substance abuse on the efficacy of treatment. We hypothesize exposure to drugs of abuse such as opioid or amphetamine contributes to the increased rate of HIV infection in substance abusers by altering the lymphoid microenvironment to facilitate infection and replication of HIV in lymphoid tissues. A major barrier that impeded investigation of the early events of HIV infection, particularly the effect of substance abuse, is the lack of an animal model that is infectible by HIV. Recently, more robust humanized mouse models such as hu-NSG mice have been developed using highly immunodeficient mice transplanted with human hematopoietic stem cells. These mice display extensive engraftment of the mouse lymphoid tissues with human T cells, B cells, macrophages and dendritic cells enabling them to be infected with HIV by the intravenous, intraperitoneal, rectal or vaginal routes. We propose to combine this novel in vivo experimental model for investigating HIV transmission with a systems biology approach to analyze and characterize the effect of drugs of abuse on the initial and subsequent cellular targets of HIV infection during the establishment of HIV infection and generate microarray data sets to identify genes modulated by opioids or meth usage that contributes to their enhancement of the initiation and spread of HIV infection. Results from this proposed study will provide a multi-scale understanding of HIV infection in humanized mice using systems biology analysis of dedicated experiments and modeling that should permit us to develop a mechanistic and quantitative grasp of how HIV infection is initiated and spread in lymphoid tissues and how it is affected by substance abuse.