AIDS, SUPERANTIGENS, AND T-CELL RECEPTOR GENES

人类感染艾滋病毒的最终后遗症是失去CD4T细胞， 免疫系统受损，易受机会性感染和 罕见的肿瘤，以及最终的死亡。尽管直接的细胞病变 HIV对CD4细胞的影响在艾滋病中无疑是重要的 发病机制，这些影响似乎并不能完全解释严重的 与这种疾病相关的免疫缺陷。 具有超抗原性的细菌、支原体和病毒的产物 属性几乎完全基于以下基础来吸引大量T细胞克隆 VBeta表达式。超抗原与T淋巴细胞的相互作用导致 无能的扩张和最终的细胞凋亡性死亡。 HIV或其他次级微生物病原体的超抗原可以 直接或间接地导致典型的艾滋病的CD4丢失 间接地通过促进病毒的传染性和复制。近期 数据表明，艾滋病与特定VBeta基因的缺失有关 克隆，HIV表现出某些VBeta克隆类型的优先感染性 艾滋病患者的T细胞容易发生凋亡，这一切都是可能的 超抗原性的表现。在此提出的研究将 确定VBeta克隆性变化是否是艾滋病的特征 通过检测VBeta参与该病的发病机制 来自所有疾病组的艾滋病毒感染患者的曲目，包括 同卵双胞胎在这种疾病中不协调和一致。此外， 艾滋病毒可能的超抗原活性将通过以下方法在体外进行评估 在HIV感染的同基因培养中检测VBeta刺激，程度 对恶性肿瘤、VBeta转基因或细菌的传染性 超抗原刺激的表达VBeta的T细胞及其效应 在胸腺器官培养中，艾滋病毒对发育中的人类免疫系统的影响。 HIV重组蛋白特异性T细胞中的VBeta基因 克隆也将被确定。体内诱导的HIV和HIV的克隆性丢失 相关蛋白质也将在SCID鼠-人胚胎中进行评估 胸腺/肝脏模型。联合研究将提供重要线索 导致艾滋病相关免疫缺陷的发病机制，并将对 对预后、随访和治疗有重要意义 以及这种流行病的病原学基础。

The ultimate sequelae of HIV infection in humans are loss of CD4 T cells, immune system compromise, susceptibility to opportunistic infections and unusual neoplasms, and eventual death. Although the direct cytopathic effects of HIV on CD4 cells are undoubtedly important in AIDS pathogenesis, these effects do not appear to fully account for the severe immunodeficiencies associated with the disease. Products of bacteria, mycoplasmas and viruses with superantigenic properties engage large sets of T cell clones almost solely on the basis of VBeta expression. T lymphocyte engagement by superantigens leads to anergy of expansion and eventual apoptotic death of the engaged cells. Superantigens of HIV or other secondary microbial pathogens may contribute to the CD4 loss that typifies AIDS either directly or indirectly by promoting infectivity and replication of the virus. Recent data suggest that AIDS is associated with deletion of specific VBeta clone, HIV exhibits preferential infectivity of certain VBeta clone types and T cells from AIDS patients are prone to apoptosis, all possible manifestations of superantigenicity. The studies proposed herein will determine whether VBeta clonal changes are characteristic of AIDS and are involved in the pathogenesis of this disease by examining VBeta repertoires in HIV-infected patients from all disease groups, including monozygotic twins discordant and concordant for this disease. Moreover, possible superantigenic activities of HIV will be assessed in vitro by examining VBeta stimulation in HIV-infected syngeneic cultures, degree of infectivity for malignant, VBeta transfected or bacterial superantigen-stimulated T cells expressing specific VBetas, and effects of HIV on the developing human immune system in thymic organ cultures. The VBeta genes represented in HIV recombinant protein-specific T cell clones will also be ascertained. In vivo induced clonal loss of HIV and related proteins will also be evaluated in the SCID mouse-human fetal thymus/liver model. The combined studies will provide important clues to the pathogenesis of AIDS-associated immunodeficiency, and will have significant implications for the prognosis, follow-up and treatment as well as etiologic basis of this epidemic disease.