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

描述(申请人提供)：根据美国的死亡率，最重要的两种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验证这一假设：9-四氢大麻酚(？9-THC)通过损害CD4T细胞的激活和功能，并通过CB1/CB2依赖和非独立的机制诱导抗病毒特异性CD8T细胞效应，从而减弱抗HIV和流感病毒的抗病毒反应。我们的研究结果表明，？9-THC显著损害：(A)宿主对流感感染的抵抗力，表现为肺病毒负荷增加，CD4和CD8 T细胞效应器减少；以及(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，以回应HIV gp120和流感相关PB1。此外，我们还发现，大麻素治疗通过抑制T细胞的激活来抑制T细胞的功能，这种机制涉及细胞内钙离子的快速和持续升高，导致T细胞无能。[Ca2]i水平的升高导致活化T细胞核因子(NFAT)的失控，并损害IL-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，具体目的如下(SA)：SA1是表征9-THC的损伤以及CB1/CB2对HIV gp120和流感相关PB1诱导的抗原特异性多功能CD8 T细胞的诱导；SA2是表征9-THC的损伤以及CB1/CB2对HIV gp120和流感相关PB1诱导的CD4 T细胞激活和功能的参与；SA3是HIV和流感攻击的体内替代模型，研究9-THC和CB1/CB2对HIV gp120和流感相关PB1诱导抗原特异性多功能CD8 T细胞应答的损害；SA4是HIV和流感攻击的体内替代模型，表征9-THC和CB1/CB2对HIV gp120和流感相关PB1应答的CD4 T细胞应答的损害和参与；SA5确定9-THC对HIV gp120和流感相关M1应答人外周血(HPB)CD8 T细胞的影响。拟议研究的意义在于，在免疫功能受损的情况下，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，艾滋病毒和癌症患者都是众所周知的大麻使用者，因为他们刺激食欲以缓解伴随艾滋病而来的消瘦综合症，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，但一个重要的数据差距是，这种做法可能在多大程度上导致免疫能力的进一步下降，以及由于继发感染导致的疾病或死亡的更快发展。 公共卫生相关性：患有艾滋病和/或癌症的患者免疫功能受损，也是公认的大麻使用者，大麻是一种免疫抑制的非法药物；艾滋病毒患者用于刺激食欲和缓解艾滋病衰竭综合征，癌症患者用于缓解癌症化疗引起的恶心。该项目评估了大麻对艾滋病毒和常见病原体流感的免疫力的影响，流感对免疫功能受损的人的发病率更高。

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.