HERV-K18 as a Risk Factor for CFIDS

HERV-K18 作为 CFIDS 的风险因素

• 批准号: 7366904
• 负责人: Brigitte T. Huber
• 金额: $ 33.22万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-24 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7366904
• 关键词: Acute; Adolescent; Affect; Alleles; Antibodies; Antigens; Biochemical; Biological Assay; Blood; Capsid; Characteristics; Childhood; Chronic Disease; Chronic Fatigue Syndrome; Class; Clinical; Clinical Treatment; Communicable Diseases; Contracts; DNA; Data; Development; Disease; Disease Progression; Epidemiologist; Epstein-Barr Virus Infections; Etiology; Freezing; Genetic; Genetic Transcription; Genotype; Grant; HERVs; Herpesviridae; Human Herpesvirus 4; Hybridomas; Immune system; Individual; Infection; Infectious Mononucleosis; Interferons; K-18 conjugate; Laboratories; Lymphokines; Measures; Monitor; Numbers; Odds Ratio; Organ; Pathogenesis; Patients; Pattern; Pediatrics; Peripheral Blood Lymphocyte; Pilot Projects; Polymerase Chain Reaction; Process; Production; Proteins; Proviruses; Psychologist; Purpose; Recording of previous events; Reporter; Research; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Risk Factors; Role; Sampling; Scientist; Serum; Simplexvirus; Statistically Significant; Superantigens; Symptoms; T-Lymphocyte; Testing; Time; Viral; Whole Blood; Work; base; chemokine; cohort; concept; env Genes; novel

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.

描述（由申请人提供）：慢性疲劳综合症（CFS）的病因尚不清楚，很可能是由多种遗传因素造成的。 EBV 感染和 IFN-a 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 可以激活人内源性逆转录病毒 HERV-K18 的 env 基因的转录。这种原病毒通常是沉默的，但当被诱导时，它会编码一种超抗原（SAg），这是一类能够解除免疫系统调节的蛋白质。 HERV-K18 env 的三个等位基因已被记录，K18.1、K18.2、K18.3，其基因产物具有 SAg 活性，但预计在生化和功能上有所不同。我们的工作假设是 HERV-K18 是 CFS 的一个危险因素。在一项初步研究中，比较了不同组的 CFS 患者和健康对照之间 HERV-K18 env 基因的等位基因和基因型分布。尽管各个队列中只有有限数量的样本，但获得的比值比具有统计显着性。对这些数据最有趣的解释是，它们为至少一组慢性疲劳综合症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，可以划分不同的 CFS 亚型。现在建议使用由联合研究者 Renee Taylor 博士收集的 400 名与 EBV 相关的 CFS 患者组成的更大队列来证实这些试点结果。获得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，还将测量活动期与疾病间歇期 HERV-K18 SAg 的表达模式。此外，将使用我们实验室开发的 T 细胞杂交瘤报告基因测定法，在体外测试该 SAg 在疾病过程中在患者外周血淋巴细胞上表达的 T 细胞刺激活性。由于 SAg 激活的 T 细胞产生大量趋化因子、淋巴因子和神经因子，因此 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途径。 CFS 是一种影响全世界大量人群的疾病，但其发病机制的潜在机制仍不清楚。疱疹病毒 EBV 和 IFN-a 已被认为与慢性疲劳综合症有关，尽管这些概念还远没有被接受。我们提出了 EBV/CFS 关联中的一个新的遗传方面，即存在某些超抗原活性不同的 HERV-K18 等位基因。