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

描述(申请人提供)：在性接触后，艾滋病毒跨越粘膜屏障，建立感染细胞团，放大最初的感染性接种，并启动随后通过淋巴和血管系统的系统性传播。一些证据表明，长期接触滥用药物与感染艾滋病毒的风险增加和进展更快有关。一大批艾滋病毒感染者是娱乐吸毒者，他们在传播感染方面发挥了重要作用，必须通过任何拟议的疗法有效治疗，以减少艾滋病毒感染的传播。通过描述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，可能会加强对这一群体的有效治疗的设计。我们假设，通过改变淋巴微环境，促进淋巴组织中艾滋病毒的感染和复制，阿片类药物或苯丙胺等滥用药物的暴露导致药物滥用者艾滋病毒感染率的增加。阻碍调查的一个主要障碍 艾滋病毒感染的早期事件，特别是药物滥用的影响，是缺乏可感染艾滋病毒的动物模型。最近，利用高度免疫缺陷的小鼠移植了人造血干细胞，建立了更强大的人源化小鼠模型，如Hu-NSG小鼠。这些小鼠表现出广泛的植入小鼠淋巴组织的人类T细胞、B细胞、巨噬细胞和树突状细胞，使它们能够通过静脉、腹膜、直肠或阴道途径感染艾滋病毒。我们建议将这一研究HIV传播的新型体内实验模型与系统生物学方法相结合，分析和表征在HIV感染建立过程中滥用药物对HIV感染的初始和后续细胞靶点的影响，并生成微阵列数据集，以识别受阿片类药物或冰毒使用调节的基因，这些基因有助于促进HIV感染的启动和传播。这项拟议研究的结果将利用专门实验和建模的系统生物学分析，提供对人源化小鼠中艾滋病毒感染的多尺度理解，这将使我们能够从机制和定量上掌握艾滋病毒感染是如何在淋巴组织中启动和传播的，以及它是如何受到药物滥用的影响的。

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.