HERV-K18 as a Risk Factor for CFIDS

描述（由申请人提供）：慢性疲劳综合征（CFS）的病因还远未了解，可能是由于多种遗传成分。EBV感染和IFN-α治疗与发病机制有关。我们的实验室已经表明，EBV感染和外源性IFN-α？，激活人内源性逆转录病毒HERV-K18的env基因的转录。这种前病毒通常是沉默的，但当被诱导时，它编码超抗原（SAg），这是一类能够解除免疫系统调节的蛋白质。已经记录了HERV-K18 env的三个等位基因，K18.1，K18.2，K18.3，其基因产物具有SAg活性，但预计在生物化学和功能上不同。我们的工作假设是HERV-K18是CFS的危险因素。在一项初步研究中，比较了不同CFS患者组和健康对照组之间HERV-K18 env基因的等位基因和基因型分布。虽然在不同的队列中只有有限数量的样本可用，但获得的比值比具有统计学意义。对这些数据最有趣的解释是，它们为至少一组CFS患者的独特病因提供了遗传证据。因此，根据患者的临床病史，可以描述CFS的不同亚型。现在建议使用由合作研究者Renee Taylor博士组装的400名与EBV相关的CFS患者的更大队列来证实这些试点结果。儿科和儿科传染病委员会认证的Ben Katz博士将对患者队列进行临床评估，遗传流行病学家和生物统计学家Inga Peter博士将监督统计分析。此外，将测量活动性疾病与间歇期期间HERV-K18 SAg的表达模式。此外，在疾病过程中在患者外周血淋巴细胞上表达的该SAg的T细胞刺激活性将使用我们实验室已经开发的T细胞杂交瘤报告基因测定进行离体测试。由于SAg激活的T细胞产生大量的趋化因子、淋巴因子和神经因子，HERV-K18 SAg的表达不仅可以影响免疫系统，还可以影响其他器官。CFS与HERV-K18等位基因或表达模式之间的正相关性将为开发这种慢性疾病的临床治疗开辟新的途径。CFS是一种影响世界范围内大量人群的疾病，但发病机制仍不清楚。疱疹病毒EBV和IFN-α已被认为与CFS有关，尽管这些概念远未被接受。我们提出了一个新的遗传方面的EBV/ CFS协会，即某些HERV-K18等位基因的存在，不同的超抗原活性。

DESCRIPTION (provided by applicant): The etiology of Chronic Fatigue Syndrome (CFS) is far from understood and is likely due to multiple genetic components. Infection with EBV and treatment with IFN-a have been implicated in the pathogenesis. Our laboratory has shown that EBV-infection, and exogenous IFN-a?, activate transcription of the env gene of a Human Endogenous Retrovirus, HERV-K18. This provirus is normally silent, but when induced it encodes a superantigen (SAg), which is a class of proteins that is capable of deregulating the immune system. Three alleles of HERV-K18 env have been documented, K18.1, K18.2, K18.3, whose gene products have SAg activity, but are predicted to differ biochemically and functionally. Our working hypothesis is that HERV-K18 is a risk factor for CFS. In a pilot study, the allele and genotype distributions of the HERV-K18 env gene were compared between various groups of CFS patients and healthy controls. Although only a limited number of samples were available in the various cohorts, the odds ratios that were obtained were statistically significant. The most intriguing interpretation of these data are that they provide genetic evidence for the unique etiology of at least one group of CFS patients. Thus, it may be possible to delineate different subtypes of CFS, depending on the clinical history of the patients. It is now proposed to substantiate these pilot results, using a much larger cohort of 400 CFS patients associated with EBV that has been assembled by the co-investigator, Dr. Renee Taylor. Dr. Ben Katz, board certified in both Pediatrics and Pediatric Infectious Diseases, will clinically evaluate the patient cohort, and Dr. Inga Peter, a genetic epidemiologist and biostatistician, will oversee the statistical analyses. In addition, the expression pattern of the HERV-K18 SAg during active disease versus intermission will be measured. Furthermore, T cell stimulatory activity of this SAg, expressed on peripheral blood lymphocytes of patients during the course of the disease, will be tested ex vivo, using a T cell hybridoma reporter assay that has been developed in our lab. Since SAg-activated T cells produce massive quantities of chemokines, lymphokines and neurokines, the expression of the HERV-K18 SAg could influence not only the immune system, but other organs as well. A positive association between CFS and either HERV-K18 alleles or expression patterns would open new avenues for the development of clinical treatments of this chronic disease. CFS is a disease that affects a significant number of people worldwide, yet the underlying mechanism(s) of pathogenesis remains unclear. The herpesvirus EBV and IFN-a have been suggested to be associated with CFS, although these concepts are far from accepted. We propose a novel genetic aspect in the EBV/ CFS association, namely the presence of certain HERV-K18 alleles that differ in their superantigen activity.