Phipps D J, Yousefi S, Branch D R
Department of Oncology Research, The Toronto Hospital Research Institute, Toronto, Ontario, Canada.
Blood. 1997 Nov 1;90(9):3603-12.
The immune system of patients infected with human immunodeficiency virus (HIV) is in a state of chronic activation; however, the nature of HIV-related immune activation is unknown. As normal T-cell activation involves early tyrosine phosphorylation induced by the T-cell antigen receptor-associated src-family protein tyrosine kinase p59(fyn(T)) (Fyn), we examined a potential role for this kinase in HIV-related immune dysfunction. We determined the relative specific kinase activity of Fyn in lysates of peripheral blood mononuclear cells from 47 normal control individuals tested negative for HIV-1 and -2, human T-cell lymphotropic virus Type I, hepatitis B virus (HBV), hepatitis C virus (HCV), and syphilis; 14 asymptomatic HIV-infected patients having near-normal CD4+ T-cell counts (350 to 980 CD4+ cells/microL); 4 patients with symptomatic acquired immunodeficiency syndrome (AIDS) (<30 CD4+ cells/microL); 13 patients having chronic infection with HBV (6 patients) or HCV (7 patients); and 6 patients with systemic lupus erythematosis (SLE). All patients with asymptomatic HIV disease were shown to have a profound increase (mean increase of 19-fold; range threefold to 56-fold increase; p = 1.33 x 10(-9)) in the relative specific kinase activity of Fyn compared to uninfected controls or patients with hepatitis or SLE. In contrast, patients with AIDS had an Fyn-specific kinase activity that was much less affected (mean increase of threefold; range onefold to sevenfold increase; p = 1.30 x 10(-5)). It was further shown that HIV infection affects the Fyn-specific kinase activity in CD8+-enriched cells, suggesting abnormal Fyn activity in both CD8+ as well as CD4+ T lymphocytes. Initial results implicate a role for the CSK protein tyrosine kinase as responsible for the abnormal Fyn kinase activity observed in HIV-infected patients. These data indicate early and chronic activation of Fyn as a unique HIV-related effect that has the potential to be diagnostic for early HIV infection and/or may serve as a prognostic indicator for advancement to full-blown AIDS. More importantly, sustained activation of the protein tyrosine kinase associated with T-cell antigen receptor function may result in, or contribute to, the immunopathogenic effects associated with HIV infection.
感染人类免疫缺陷病毒（HIV）的患者免疫系统处于慢性激活状态；然而，与HIV相关的免疫激活的本质尚不清楚。由于正常T细胞激活涉及由T细胞抗原受体相关的src家族蛋白酪氨酸激酶p59(fyn(T))（Fyn）诱导的早期酪氨酸磷酸化，我们研究了该激酶在与HIV相关的免疫功能障碍中的潜在作用。我们测定了47名HIV-1和-2、人类嗜T细胞病毒I型、乙型肝炎病毒（HBV）、丙型肝炎病毒（HCV）和梅毒检测均为阴性的正常对照个体外周血单核细胞裂解物中Fyn的相对特异性激酶活性；14名无症状HIV感染患者，其CD4+T细胞计数接近正常（350至980个CD4+细胞/微升）；4名有症状的获得性免疫缺陷综合征（AIDS）患者（<30个CD4+细胞/微升）；13名慢性感染HBV（6名患者）或HCV（7名患者）的患者；以及6名系统性红斑狼疮（SLE）患者。与未感染的对照或患有肝炎或SLE的患者相比，所有无症状HIV疾病患者的Fyn相对特异性激酶活性均显著增加（平均增加19倍；范围为三倍至56倍增加；p = 1.33 x 10(-9)）。相比之下，AIDS患者的Fyn特异性激酶活性受影响较小（平均增加三倍；范围为一倍至七倍增加；p = 1.30 x 10(-5)）。进一步表明，HIV感染会影响富含CD8+细胞中的Fyn特异性激酶活性，提示CD8+以及CD4+T淋巴细胞中Fyn活性异常。初步结果表明，CSK蛋白酪氨酸激酶在HIV感染患者中观察到的异常Fyn激酶活性中起作用。这些数据表明Fyn的早期和慢性激活是一种独特的与HIV相关的效应，有可能用于早期HIV感染的诊断和/或作为发展为全面AIDS的预后指标。更重要的是，与T细胞抗原受体功能相关的蛋白酪氨酸激酶的持续激活可能导致或促成与HIV感染相关的免疫致病效应。
