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

药物滥用对 HIV 感染的体内影响的系统生物学分析

• 批准号: 8685627
• 负责人: HARRIS GOLDSTEIN
• 金额: $ 3.46万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8685627
• 关键词: Acute; Affect; Amphetamines; Animal Model; Animals; Anti-Retroviral Agents; Antiretroviral resistance; Automobile Driving; B-Lymphocytes; Behavior; Biological; Cells; Chronic; Computational Biology; Data Analyses; Data Set; Dendritic Cells; Development; Disease; Disease Progression; Drug user; Engraftment; Ensure; Epidemic; Event; Experimental Models; Exposure to; Faculty; Functional disorder; Genes; Genetic Transcription; HIV; HIV Infections; Hematopoietic stem cells; Human; Immunodeficient Mouse; Immunology; Individual; Infection; Intravenous; Investigation; Leukocytes; Lymphatic System; Lymphoid; Lymphoid Tissue; Macaca; Microbiology; Modality; Modeling; Mus; Opioid; Performance; Play; Population; Prophylactic treatment; Recreational Drugs; Regimen; Research; Research Personnel; Risk; Risk Factors; Role; Route; SIV; Staging; Substance abuse problem; System; Systems Biology; T-Lymphocyte; Therapeutic; Transplantation; Treatment Efficacy; Vaccination; Vagina; Vascular System; cellular targeting; cohort; cost; design; drug of abuse; effective therapy; grasp; high risk sexual behavior; in vivo; insight; intraperitoneal; macrophage; meetings; member; mouse model; novel; prevent; recreational drug use; rectal; research study; substance abuser; synergism; therapy development; transmission process

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.

描述（由申请人提供）：性接触后，HIV 穿过粘膜屏障，建立受感染细胞的病灶，从而放大最初的感染性接种物，并启动随后通过淋巴和血管系统的全身传播。多项证据表明，长期接触滥用药物与艾滋病毒感染和更快进展的风险增加有关。大量艾滋病毒感染者是娱乐性吸毒者，在传播感染方面发挥着重要作用，必须通过任何拟议的治疗方案进行有效治疗，以减少艾滋病毒感染的传播。通过描述物质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，可能会加强针对这一人群的有效治疗设计。我们假设，接触阿片类药物或安非他明等滥用药物会改变淋巴微环境，促进艾滋病毒在淋巴组织中的感染和复制，从而导致药物滥用者艾滋病毒感染率增加。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，是缺乏可感染HIV的动物模型。最近，使用移植了人类造血干细胞的高度免疫缺陷小鼠开发了更强大的人源化小鼠模型，例如 hu-NSG 小鼠。这些小鼠的小鼠淋巴组织广泛植入了人类 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内、腹膜内、直肠或阴道途径感染 HIV。我们建议将这种用于研究艾滋病毒传播的新型体内实验模型与系统生物学方法相结合，以分析和表征在艾滋病毒感染建立过程中滥用药物对艾滋病毒感染的初始和后续细胞目标的影响，并生成微阵列数据集来识别阿片类药物或冰毒使用调节的基因，这些基因有助于增强艾滋病毒感染的引发和传播。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，对人源化小鼠的艾滋病毒感染提供多尺度的了解，这将使我们能够对艾滋病毒感染如何在淋巴组织中引发和传播以及它如何受到药物滥用的影响有一个机制和定量的了解。