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

描述（由申请人提供）：在性接触后，HIV穿过粘膜屏障，建立一个受感染细胞的病灶，扩大最初的感染接种，并通过淋巴和血管系统开始随后的全身传播。若干证据表明，长期接触滥用药物与艾滋病毒感染的风险增加和进展速度加快有关。在传播感染方面起主要作用的大量娱乐性药物使用者艾滋病毒感染者必须通过任何拟议的治疗方案得到有效治疗，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，有助于增加药物滥用者的HIV感染率。阻碍调查的主要障碍

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. PUBLIC HEALTH RELEVANCE: In order reduce HIV transmission in the population of substance abusers, we need to understand the mechanisms by which substance abuse enhances HIV infection and increases transmission. We propose to use combine experimental results using a novel humanized mouse model consisting of mice populated with human hematopoietic stem cells with systems biology analysis to study the mechanism by which substance abuse increases HIV transmission and accelerates disease course.