COCAINE SYNERGIZES WITH T CELL ACTIVATION AS A COFACTOR FOR HIV INFECTION

可卡因与 T 细胞激活协同作用，作为 HIV 感染的辅助因子

基本信息

批准号：
7488444
负责人：
GAYLE COCITA BALDWIN
金额：
$ 33.96万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7488444
关键词：
5-(6)-carboxyfluorescein diacetate succinimidyl ester Acquired Immunodeficiency Syndrome Acute Address Adenovirus Vector Animal Model Animals Antigens Antiviral Agents Area Biological Assay Blood specimen CD34 gene CD4 Positive T Lymphocytes CD4/CD8 ratio procedure CD8B1 gene Cell Count Cells Cessation of life Characteristics Chimera organism Chronic Clinical Cocaine Cocaine Abuse Complex Control Animal Crack Cocaine Dendritic Cells Development Dose Drug Exposure Drug abuse Event Exhibits Exposure to Frequencies Generations HIV Hematopoiesis Highly Active Antiretroviral Therapy Human Human Development Hybrids Immune Immune Targeting Immune response Immune system Immunity Immunologic Deficiency Syndromes Implant In Vitro Infection Injection of therapeutic agent Interleukin-10 Interleukin-12 Interleukin-13 Knockout Mice Label Leukocytes Longevity Lymphoid Maps Measures Mediating Memory Modeling Monitor Mus Needle Sharing Newborn Infant Non obese Numbers Organ Outcome Outcome Measure Pathogenesis Pathway interactions Peripheral Blood Lymphocyte Peritoneal Peritoneum Pharmaceutical Preparations Phenotype Play Predisposition Principal Investigator Process Production Proliferating Public Health Rate Reagent Reporter Reporting Research Reverse Transcriptase Polymerase Chain Reaction Risk Risk Factors Role SCID Mice Saline Serotyping Spleen Stem cells Substance abuse problem T-Cell Activation T-Lymphocyte Techniques Testing Time Umbilical Cord Blood Up-Regulation Vaccinated Vaccines Viral Viral Load result Viral Pathogenesis Virus Virus Diseases Virus Replication Week antigen challenge chemokine cofactor cytokine design diabetic drug of abuse high risk sexual behavior immunodeficient mouse model implantation in vitro Assay in vitro Model in vivo insight neutralizing antibody neutralizing monoclonal antibodies next generation novel peripheral blood prevent programs receptor reconstitution research study response transmission process virus infection mechanism

项目摘要

DESCRIPTION (provided by applicant): Infection by HIV and progression to AIDS involves a complex interaction between the host's immune system, HIV, and a variety of cofactors. Amongst these cofactors, epidemiological evidence supports a role for "crack" cocaine as an independent risk factor for the development of HIV and AIDS. Corroborating these findings, we have shown that exposure to cocaine enhances viral infection, increases systemic viral load, and the loss of CD4+ cells in vivo in immudeficient mice engrafted wtih human peripheral blood leucocytes. Understanding how cocaine mediates these effects is the major focus of this proposal. As we have recently shown that antigen (Ag) presentation by dendritic cells (DC) leads to the upregulation of CD4 and chemokine coreceptors on responder T cells and enhances their susceptibility to infection by HIV, we have hypothesized that cocaine modulates this process, producing a unique interaction/synergy that increases susceptibility to, and, replication of HIV. To test this hypothesis, we propose the following specific aims: Aim 1: To investigate how acute exposure to cocaine during an Ag-challenge promotes HIV infection of T cells in vivo in the huPBL-NOD-SCID/IL2rg-null model. Aim 2: To determine the effects of habitual exposure to cocaine on viral pathogenesis and immune responsiveness in a NOD-SCID/IL2rg-null mouse/human hybrid model of chronic HIV infection. Short-term studies in the huPBL-NOD-SCID/IL2rg-null model proposed for Aim 1 will focus on an infectious Ag challenge as a cofactor for increasing HIV infection and the mechanisms by which cocaine enhances HIV infection of the resulting Ag-specific CD4+ and CD8+ T cells. In addition, these studies will provide important insight into the capacity for an HIV-compromised immune system to mount effective vaccine responses. Finally, as proposed for Aim 2, the development and testing of stable mouse-human chimeras that exhibit functional immune systems will be used to extend our observations into a model of chronic HIV infection and habitual cocaine abuse, providing one of the most flexible and relevant animal models in which to study the in vivo effects of habitual drug abuse on human immunity and HIV infection.

描述（由申请人提供）：艾滋病毒感染和艾滋病的进展涉及宿主的免疫系统，艾滋病毒和多种辅助因子之间的复杂相互作用。在这些辅助因子中，流行病学证据支持可卡因作为艾滋病毒和艾滋病发展的独立危险因素的作用。为了证实这些发现，我们已经表明，接触可卡因会增强病毒感染，增加全身病毒载量，并在不足的小鼠中体内CD4+细胞的丢失植入了WTIH WTIH人类外周血血清细胞。了解可卡因如何介导这些影响是该提议的主要重点。正如我们最近表明的那样，树突状细胞（DC）抗原（Ag）呈递导致CD4和趋化因子copector在响应者T细胞上的上调，并增强了通过HIV感染的敏感性，我们假设可可蛋白会调节这一过程，从而使这种独特的相互作用/协同/协同化，从而提高了敏感性，从而使HIV变得更高，并重复了HIV。为了检验这一假设，我们提出了以下特定目的：目标1：研究在Ag挑战期间急性暴露于可卡因如何促进HUPBL-NOD-SCID/IL2RG-NULL模型中T细胞在体内的HIV感染。目标2：确定可卡因暴露于慢性HIV感染的点头/IL2RG无效小鼠/人类杂交模型中可卡因对病毒发病机理和免疫反应性的影响。在HUPBL-NOD-SCID/IL2RG-NULL模型中，提出的针对AIM 1的短期研究将集中于感染性AG挑战，作为增加HIV感染的辅助因子，以及可卡因增强可卡因的HIV感染所得AG AG特异性CD4+和CD8+ T细胞的机制。此外，这些研究将提供对HIV庞大的免疫系统实现有效疫苗反应的能力的重要见解。最后，正如AIM 2提出的那样，表现出功能性免疫系统的稳定小鼠人类嵌合体的开发和测试将用于将我们的观察扩展到慢性HIV感染和习惯性可卡因滥用模型中，从而提供了最具灵活和相关的动物模型之一，在其中研究了习惯性药物滥用对人类免疫的体内影响和HIV的影响。