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

• 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
• 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

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HIV和流感。这5年研究计划的总体目标是检验假设：？9-四氢大麻醇（？9-THC）通过损害CD 4 + T细胞活化和功能以及通过CB 1/CB 2依赖性和非依赖性机制引发抗病毒特异性CD 8 + T细胞效应物来减弱针对HIV和流感病毒的抗病毒应答。我们的调查结果显示？9-THC明显损害：（a）宿主对流感感染的抗性，如通过增加的肺病毒负荷和降低的CD 4+和CD 8 + T细胞效应物所证明的;和（B）响应于HIV gp 120和流感相关的PB 1的体外CD 8 + T细胞功能、细胞毒性T淋巴细胞活性和干扰素3产生。此外，我们发现大麻素治疗通过涉及细胞内钙[Ca+2]i快速和持续升高的机制损害T细胞活化，从而抑制T细胞功能，导致T细胞无反应性。[Ca+2]i水平的升高导致活化T细胞核因子（NFAT）的失调，并损害白细胞介素-2和其他NFAT调节的细胞因子的转录。另外的结果表明，CB 1-/-/CB 2-/-小鼠在清除流感病毒方面比野生型小鼠明显更有效，暗示了CB 1和/或CB 2在病毒宿主抗性中的作用。基于上述研究结果，我们将测试我们的假设，使用新的细胞为基础的模型，具有以下具体目标（SA）：SA 1是表征损伤？9-THC，和CB 1/CB 2的参与，对抗原特异性多功能CD 8 + T细胞的诱导响应HIV gp 120和流感相关的PB 1; SA 2的特点是损害？9-THC，和CB 1/CB 2的参与，对CD 4 + T细胞活化和功能诱导的HIV gp 120和流感相关的PB 1; SA 3是在体内替代模型的HIV和流感的挑战，表征损害？9-THC，并参与CB 1/CB 2，对抗原特异性多功能CD 8 + T细胞对HIV gp 120和流感相关PB 1的应答的诱导; SA 4是在体内HIV和流感挑战的替代模型中，以表征由？9-THC和CB 1/CB 2的参与对CD 4 + T细胞对HIV gp 120和流感PB 1的应答的影响;以及SA 5是确定9-THC对多功能人外周血（HPB）CD 8 + T细胞应答HIV gp 120和流感相关M1的产生的影响。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感染包括流感在内的传染性病原体。此外，众所周知，艾滋病毒和癌症患者使用大麻来刺激食欲以减轻伴随艾滋病的消耗综合征，并作为止吐剂以减轻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，但一个重要的数据缺口涉及这种做法可能导致免疫能力进一步下降以及继发感染导致疾病或死亡率更快进展的程度。 公共卫生关系：患有艾滋病和/或癌症的患者免疫力受损，并且也是大麻的公认使用者，大麻是一种具有免疫抑制作用的非法药物;艾滋病毒患者刺激食欲和减轻艾滋病消耗综合征，癌症患者减轻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免疫力的影响，流感以较高的发病率折磨免疫受损的个人。