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艾滋病毒和流感。这个5年研究计划的总体目标是检验假设：？9-tetrahydrocannbinol (?9-THC)通过损害CD4+ T细胞的激活和功能，以及通过CB1/ cb2依赖性和非依赖性机制激发抗病毒特异性CD8+ T细胞效应，减弱对HIV和流感病毒的抗病毒应答。我们的研究结果表明？9-四氢大麻酚显著损害：(a)宿主对流感感染的抵抗力，这可以通过肺部病毒负荷增加和CD4+和CD8+ T细胞效应物减少来证明；(b) CD8+ T细胞功能、细胞毒性T淋巴细胞活性和干扰素3在体外对HIV gp120和流感相关PB1的反应。此外，我们发现大麻素治疗通过一种机制损害T细胞的激活，这种机制涉及细胞内钙[Ca+2]i的快速和持续升高，导致T细胞能量增加，从而抑制T细胞功能。[Ca+2]i水平的升高导致活化T细胞（NFAT）核因子的失调，并损害白细胞介素-2和其他NFAT调节的细胞因子的转录。其他结果表明，CB1-/-/CB2-/-小鼠清除流感病毒的效率明显高于野生型小鼠，这表明CB1和/或CB2在病毒宿主抗性中发挥了作用。基于上述发现，我们将使用新的基于细胞的模型来验证我们的假设，其具体目的如下：9-THC和CB1/CB2参与抗原特异性多功能CD8+ T细胞对HIV gp120和流感相关PB1的应答；SA2是用？9-THC和CB1/CB2参与HIV gp120和流感相关PB1诱导的CD4+ T细胞活化和功能SA3在HIV和流感攻击的体内替代模型中，通过？9-THC和CB1/CB2参与激发抗原特异性多功能CD8+ T细胞对HIV gp120和流感相关PB1的反应；SA4在HIV和流感攻击的体内替代模型中，通过？9-THC和CB1/CB2参与CD4+ T细胞对HIV gp120和流感PB1的应答和SA5是为了确定9-THC对多功能人外周血（HPB） CD8+ T细胞生成的影响，以响应HIV gp120和流感相关M1。拟议研究的意义在于，在免疫功能低下状态下，感染艾滋病毒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是为了刺激食欲，减轻艾滋病伴随的消瘦综合征，并作为一种止吐剂，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，但一个重要的数据缺口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和继发感染导致疾病更快发展或死亡。