IMMUNE REACTIVITY AND ONCOGENIC VIRUS INFECTIONS

病毒-白细胞相互作用对感染的结果至关重要， 潜在致癌病毒。 白细胞限制了两者的复制 病毒和由病毒转化的细胞。 然而，病毒也可能 在白细胞中复制并改变其功能，抑制有效的 反应 该提案将研究潜在的 致癌人类疱疹病毒与人类白细胞。 巨细胞病毒是人类疾病的主要原因，作为致畸剂， 输血或免疫抑制后的机会性病原体， 也可能是致癌物质 我们已经证明CMV具有强有力的 对白细胞功能免疫抑制作用。 这种机制 将探索CMV诱导的低反应性。 的功能评定 特定的白细胞亚群及其相互作用将在 体内和体外。 将尝试纠正或重建 CMV诱导的缺陷性白细胞反应。 CMV-白细胞相关性将 也可用于帮助开发CMV伪源的快速诊断检测 感染的粒细胞中。 单纯疱疹病毒也可能与人类有复杂的相互作用 白细胞 我们建立了单纯疱疹病毒持续感染的动物模型 感染人T淋巴母细胞。 这种持续性感染可能是 生产性或非生产性，取决于体外操作。 添加抗病毒药物（抗体、干扰素、阿昔洛韦）或 温度升高可导致非生产性感染。 去除 抗病毒药、降低温度、添加植物血凝素或 5-氮杂胞苷可诱导生产性感染。 的机制 这些事件将在体外进行探索，并将尝试 确定甲基化在维持 非生产性感染。 原位分子杂交技术将 用于确定在感染期间被感染的细胞数量。 生产性和非生产性感染。 同样的技术将被用于 调查最近的建议，某些人类疾病，例如， 白塞氏综合征与淋巴细胞携带潜伏性疱疹有关 单纯DNA 我们的疱疹模型也将用于探索相互作用 抗病毒药物和持续性感染之间的联系

Virus-leukocyte interactions are critical to the outcome of infections with potentially oncogenic viruses. Leukocytes limit the replication of both viruses and cells transformed by viruses. However, viruses may also replicate in leukocytes and alter their function, inhibiting an effective response. This proposal will study the interactions of potentially oncogenic human herpesviruses with human leukocytes. Cytomegalovirus is a major cause of human disease, as a teratogen, opportunistic pathogen following blood transfusions or immunosuppression, and as a possible oncogen. We have demonstrated that CMV has a potent immunosuppressive effect onleukocyte function. The mechanisms of this CMV-induced hyporesponsiveness will be explored. Functional evaluation of specific leukocyte subsets and their interactions will be undertaken in vivo and in vitro. Attempts will be made to correct or reconstruct CMV-induced defective leukocyte responses. CMV-leukocyte associations will also be exploited to help develop rapid diagnostic assays for CMV artigens in infected granulocytes. Herpes simplex virus may also have complex interactions with human leukocytes. We have established a model of herpes simplex virus persistent infection of human T lymphoblasts. This persistent infection can either be productive or non-productive, depending on manipulations in vitro. Addition of antiviral agents (antibody, interferon, acyclovir) or temperature elevation can result in non-productive infection. Removal of antivirals, lowering of temperature, addition of phytohemagglutinin or 5-azacytidine can induce productive infection. The mechanisms underlying these events will be explored in vitro, and attempts will be made to determine the importance of methylation in the maintenance of non-productive infections. In situ molecular hybridization techniques will be used to determine the numbers of cells that are infected during productive and non-productive infections. The same techniques will be used to investigate the recent suggestion that certain human diseases, e.g. Behcet's syndrome, are associated with lymphocytes carrying latent herpes simplex DNA. Our herpes model will also be used to explore interactions between antiviral agents and persistent infections.