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）：HIV 感染和艾滋病进展涉及宿主免疫系统、HIV 和多种辅助因子之间复杂的相互作用。在这些辅助因素中，流行病学证据支持“快克”可卡因作为艾滋病毒和艾滋病发展的独立危险因素。我们证实了这些发现，在移植了人外周血白细胞的免疫缺陷小鼠中，接触可卡因会增强病毒感染，增加全身病毒载量，并导致体内 CD4+ 细胞的损失。了解可卡因如何调节这些影响是该提案的主要焦点。正如我们最近表明，树突状细胞 (DC) 呈递抗原 (Ag) 会导致应答 T 细胞上 CD4 和趋化因子辅助受体的上调，并增强其对 HIV 感染的易感性，我们假设可卡因调节这一过程，产生独特的相互作用/协同作用，增加艾滋病毒的易感性和复制。为了检验这一假设，我们提出以下具体目标：目标 1：在 huPBL-NOD-SCID/IL2rg-null 模型中研究 Ag 攻击期间急性接触可卡因如何促进体内 T 细胞的 HIV 感染。目标 2：在慢性 HIV 感染的 NOD-SCID/IL2rg 缺失小鼠/人类混合模型中确定习惯性接触可卡因对病毒发病机制和免疫反应的影响。针对目标 1 提出的 huPBL-NOD-SCID/IL2rg-null 模型的短期研究将重点关注传染性 Ag 挑战作为增加 HIV 感染的辅助因子，以及可卡因增强由此产生的 Ag 特异性 CD4+ 的 HIV 感染的机制和 CD8+ T 细胞。此外，这些研究将为了解艾滋病毒受损的免疫系统发起有效疫苗反应的能力提供重要见解。最后，正如目标 2 所提出的，开发和测试表现出功能性免疫系统的稳定小鼠-人嵌合体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，从而提供最灵活和相关的模型之一。动物模型，用于研究习惯性药物滥用对人体免疫和艾滋病毒感染的体内影响。