THC impairment of CD4/CD8 T cell-mediated host resistance to HIV and influenza

THC 损害 CD4/CD8 T 细胞介导的宿主对 HIV 和流感的抵抗力

基本信息

批准号：
7934666
负责人：
Norbert E Kaminski
金额：
$ 29.67万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7934666
关键词：
Acquired Immunodeficiency Syndrome Antiemetics Antigens Antiviral Agents Antiviral Response Area Attenuated CD4 Positive T Lymphocytes CD8B1 gene Calcium Cancer Patient Cannabinoids Cannabis Cell Line Cell model Cell physiology Cells Chemotherapy-Oncologic Procedure Competence Cytotoxic T-Lymphocytes Data Dendritic Cells Disease Progression Epitopes Exhibits Gene Expression Generations Genetic Transcription Goals HIV HIV Envelope Protein gp120 HIV Wasting Syndrome Host resistance Human IL2 gene Illicit Drugs Immune Immunity Immunocompromised Host Immunosuppressive Agents Impairment In Vitro Incidence Individual Influenza Interferons Interleukin-2 Invaded Ionophores Lead Lung Malignant Neoplasms Mediating Modeling Molecular Mus Nausea Patients Peptides Play Production Research Role T cell anergy T cell response T-Cell Activation T-Lymphocyte Testing Time Tumor Necrosis Factor-alpha Tumor Necrosis Factors United States Viral Viral Load result Viral Physiology Virus Diseases Wasting Syndrome Wild Type Mouse base cannabinoid receptor cytokine extracellular immunogenic immunoregulation in vivo increased appetite influenzavirus mortality novel nuclear factors of activated T-cells pathogen peripheral blood public health relevance receptor response secondary infection

项目摘要

DESCRIPTION (provided by applicant): The two most important viral pathogens, based on mortality in the United States are HIV and influenza. The overall goal of this 5 year research plan is to test the hypothesis: ?9-tetrahydrocannbinol (?9-THC) attenuates antiviral responses against HIV and influenza virus through impairment of CD4+ T cell activation and function, and elicitation of antiviral specific CD8+ T cell effectors through CB1/CB2-dependent and -independent mechanisms. Our findings show that ?9-THC markedly impairs: (a) host resistance to influenza infection as evidenced by increased lung viral burden and decreased CD4+ and CD8+ T cell effectors; and (b) CD8+ T cell function, cytotoxic T lymphocyte activity and interferon 3 productions in vitro, in response to HIV gp120 and influenza-associated PB1. In addition, we show that cannabinoid treatment suppresses T cell function by impairing T cell activation via a mechanism involving rapid and sustained elevation in intracellular calcium [Ca+2]i, leading to T cell anergy. The rise in [Ca+2]i levels causes deregulation of the nuclear factor of activated T cells (NFAT) and impairs transcription of interleukin-2 and other NFAT-regulated cytokines. Additional results show that CB1-/-/CB2-/- mice are markedly more efficient in clearing influenza virus than wild type mice implicating a role for CB1 and/or CB2 in viral host resistance. Based on the above findings we will test our hypothesis using novel cell-based models with the following specific aims (SA): SA1 is to characterize impairment by ?9-THC, and the involvement of CB1/CB2, on the elicitation of antigen-specific multifunctional CD8+ T cells in response to HIV gp120 and influenza-associated PB1; SA2 is to characterize the impairment by ?9-THC, and the involvement of CB1/CB2, on CD4+ T cell activation and function induced by HIV gp120 and influenza-associated PB1; SA3 is in an in vivo surrogate model of HIV and influenza challenge, to characterize the impairment by ?9-THC, and involvement of CB1/CB2, on the elicitation of antigen-specific multifunctional CD8+ T cell responses to HIV gp120 and influenza-associated PB1; SA4 is in an in vivo surrogate model of HIV and influenza challenge, to characterize the impairment by ?9-THC, and involvement of CB1/CB2, on the CD4+ T cell response to HIV gp120 and influenza PB1; and SA5 is to determine the effect of 9-THC on the generation of multifunctional human peripheral blood (HPB) CD8+ T cells in response to HIV gp120 and influenza-associated M1. The significance of the proposed studies is that in their immunocompromised state, those infected with HIV or cancer patients are especially susceptible to infectious pathogens including influenza. Moreover, HIV and cancer patients are well known users of cannabis for stimulating appetite to alleviate the wasting syndrome that accompanies AIDS and as an antiemetic to relieve the nausea produced by cancer chemotherapy. In spite of the many HIV and cancer patients utilizing cannabis multiple times daily, an important data gap concerns the extent to which this practice may lead to a further diminution in immune competence and a more rapid progression of disease or mortality due to secondary infections. PUBLIC HEALTH RELEVANCE: Patients suffering from AIDS and/or cancer are immune compromised and are also well-established users of cannabis, an illicit drug that is immunosuppressive; HIV patients to stimulate appetite and alleviate AIDS wasting syndrome and cancer patients to relieve nausea produced by cancer chemotherapy. This project assesses the consequences of cannabis on immunity against HIV and the common pathogen, influenza, which afflicts immune compromised individuals at a higher incidence.

描述（由申请人提供）：根据美国的死亡率，两种最重要的病毒病原体是艾滋病毒和流感。这项为期 5 年的研究计划的总体目标是检验以下假设：9-四氢大麻酚 (?9-THC) 通过损害 CD4+ T 细胞的活化和功能并引发抗病毒特异性 CD8+ T 来减弱针对 HIV 和流感病毒的抗病毒反应通过 CB1/CB2 依赖和独立机制的细胞效应器。我们的研究结果表明，9-THC 显着损害： (a) 宿主对流感感染的抵抗力，如肺部病毒负荷增加和 CD4+ 和 CD8+ T 细胞效应器减少所证明； (b) CD8+ T 细胞功能、细胞毒性 T 淋巴细胞活性和体外干扰素 3 的产生，以响应 HIV gp120 和流感相关 PB1。此外，我们发现大麻素治疗通过细胞内钙 [Ca+2]i 快速持续升高的机制损害 T 细胞活化来抑制 T 细胞功能，从而导致 T 细胞无反应性。 [Ca+2]i 水平升高导致活化 T 细胞核因子 (NFAT) 失调，并损害白细胞介素 2 和其他 NFAT 调节的细胞因子的转录。其他结果表明，CB1-/-/CB2-/- 小鼠在清除流感病毒方面明显比野生型小鼠更有效，这表明 CB1 和/或 CB2 在病毒宿主抵抗中发挥作用。基于上述发现，我们将使用具有以下特定目标 (SA) 的新型细胞模型来检验我们的假设：SA1 是表征 9-THC 造成的损伤，以及 CB1/CB2 的参与，引发抗原-响应 HIV gp120 和流感相关 PB1 的特异性多功能 CD8+ T 细胞； SA2 旨在表征 9-THC 以及 CB1/CB2 的参与对 HIV gp120 和流感相关 PB1 诱导的 CD4+ T 细胞活化和功能的损害； SA3 是 HIV 和流感攻击的体内替代模型，以表征 9-THC 以及 CB1/CB2 的参与对 HIV gp120 和流感相关抗原特异性多功能 CD8+ T 细胞反应的损害PB1； SA4 是 HIV 和流感攻击的体内替代模型，用于表征 9-THC 以及 CB1/CB2 参与对 CD4+ T 细胞对 HIV gp120 和流感 PB1 反应的损害； SA5 旨在确定 9-THC 对响应 HIV gp120 和流感相关 M1 的多功能人外周血 (HPB) CD8+ T 细胞的生成的影响。拟议研究的意义在于，在免疫功能低下的状态下，艾滋病毒感染者或癌症患者特别容易受到包括流感在内的传染性病原体的影响。此外，众所周知，艾滋病毒和癌症患者使用大麻来刺激食欲，缓解艾滋病伴随的消耗综合症，并作为止吐剂来缓解癌症化疗产生的恶心。尽管许多艾滋病毒和癌症患者每天多次使用大麻，但重要的数据差距涉及这种做法可能在多大程度上导致免疫能力进一步下降以及继发感染导致的疾病或死亡率更快进展。公共卫生相关性：患有艾滋病和/或癌症的患者免疫功能低下，而且也是大麻（一种具有免疫抑制作用的非法药物）的长期使用者； HIV患者可刺激食欲并缓解艾滋病消耗综合症，癌症患者可缓解癌症化疗产生的恶心。该项目评估大麻对艾滋病毒和常见病原体流感的免疫力的影响，流感对免疫功能低下的个体的发病率较高。