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：
8265686
负责人：
Norbert E Kaminski
金额：
$ 28.72万
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/8265686
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 Infections 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 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）：基于美国死亡率的两种最重要的病毒病原体是艾滋病毒和流感。这项5年研究计划的总体目标是检验假设：？9-四氢胆料（？9-THC）通过CD4+ T细胞激活和功能损害降低了针对HIV和HIV和流感病毒的抗病毒反应，以及通过CB1/CB1/CB2依赖性和-Indepentent and-Indepentent and-Indepentent和-Indepentent和-Independent and-Indeptent and-Indentent and-Indentent and-Indentent and-Indentent and-Indeptent。我们的发现表明，9-thc显着损害：（a）宿主对流感感染的抗性，这可以通过增加的肺病毒负担和减轻CD4+和CD8+ T细胞效应子证明；（b）CD8+ T细胞功能，细胞毒性T淋巴细胞活性和干扰素3在体外，响应HIV GP120和与流感相关的PB1。此外，我们表明大麻素治疗通过涉及细胞内钙快速且持续升高的机制来抑制T细胞功能[Ca+2] I，从而导致T细胞消极。 [Ca+2] I水平的升高导致活化T细胞（NFAT）的核因子的放松管制，并损害白介素-2和其他NFAT调节的细胞因子的转录。其他结果表明，与野生型小鼠相比，CB1 - / - /CB2 - / - 小鼠在清除流感病毒方面的效率明显更高，而野生型小鼠在病毒宿主抗性中涉及CB1和/或CB2的作用。根据上述发现，我们将使用具有以下特定目标（SA）的新型基于细胞的模型（SA1：9-THC表征损伤，以及CB1/CB2的参与，就抗抗原特异性多功能CD8+ T细胞的启发来响应HIV GP120和Impainza-sassiped PB1; SA2是通过“ 9-THC”表征损伤，以及CB1/CB2的参与，在CD4+ T细胞激活和由HIV GP120诱导的功能以及与流感相关的PB1上诱导的功能； SA3是在体内替代艾滋病毒和流感挑战的体内替代模型，以表征9-thc的损害，而CB1/CB2的参与是在启发抗原特异性的多功能CD8+ T细胞对HIV GP120和HIV GP120和流感型型型型PB1的启发中的参与； SA4是在CD4+ T细胞对HIV GP120和流感PB1的反应上，在体内替代HIV和流感挑战的体内替代模型，以表征9-THC的损害，并参与CB1/CB2。 SA5是确定9-THC对响应HIV GP120和与流感相关的M1的多功能人外周血（HPB）CD8+ T细胞产生的影响。拟议的研究的重要性是，在其免疫功能低下的状态下，感染HIV或癌症患者的患者特别容易受到包括流感在内的传染病。此外，艾滋病毒和癌症患者是众所周知的大麻使用者，可刺激食欲，以减轻伴随艾滋病伴随的浪费综合征，并作为一种抗体，以减轻癌症化学疗法产生的恶心。尽管每天多次使用大麻的艾滋病毒和癌症患者，但重要的数据差距仍涉及这种做法可能导致免疫能力进一步降低的程度以及由于继发感染而导致的疾病或死亡率更快。公共卫生相关性：患有艾滋病和/或癌症的患者免疫受到损害，也是大麻的成熟使用者，这是一种免疫抑制的非法药物；艾滋病毒患者刺激食欲并减轻艾滋病浪费综合征和癌症患者，以减轻癌症化学疗法产生的恶心。该项目评估了大麻对艾滋病毒免疫力和常见病原体流感的后果，后者遭受了较高发病率的免疫损害个体的影响。