The Relationship of XMRV to Functional Status and Co-infections in Chronic Fatigu

描述(申请人提供)：慢性疲劳综合症(CFS)是一种疾病，特征是长期疲劳，记忆力或注意力受损，喉咙痛，淋巴结压痛，肌肉疼痛，多关节疼痛，新的头痛，睡眠不清新，和运动不耐受。虽然慢性疲劳综合征的病因(S)尚未确定，但一些疫情的爆发涉及感染性病因学。已有多种病原体在CFS患者个体中被报道，或在CFS患者中比对照组更常见，包括各种类型的病毒。CFS患者的免疫系统既表现为慢性激活，又表现为免疫功能障碍。最近，一种新的人类逆转录病毒XMRV(异嗜性小鼠白血病病毒相关病毒)在很大比例的CFS患者中被检测到，但在健康受试者中只有4%。我们计划通过检查以前没有筛查过XMRV存在的暴发队列，来了解更多关于XMRV和其他病原体与CFS的关联。可能与XMRV相关的其他病毒、微生物和寄生虫也将通过使用全微生物DNA微阵列进行检测。我们将确定XMRV和/或其他病原体的存在是否与1985年纽约农村暴发期间患病的个人的当前健康状况有关。假设纽约队列中的大多数成员都感染了XMRV，我们将扩增并测序从40名1985年儿童时期患病的人的血细胞中提取的XMRV外膜基因。我们还将对内华达州队列中已知的XMRV感染程度较高的80名受试者的外膜基因进行测序。我们将检查内华达州和纽约XMRV变异体之间的系统发育关系，并观察是否有任何氨基酸替换与受试者当前的健康状态相关。我们还将研究XMRV和XMRV蛋白表达在运动不耐受现象中的可能联系。我们将在连续运动试验引起的症状恶化之前和之后检查XMRV感染的CFS患者。我们将确定炎性细胞因子、生长因子和一氧化氮的增加或血细胞变化是否与体能下降的程度相关，这可以在诱发劳后不适后进行的第二次运动测试中测量到。所有这些实验都将旨在评估特定的XMRV序列和表达水平是否在CFS患者的症状中发挥作用，并检测损害他们体力活动的残疾的可能潜在机制。 公共卫生相关性：慢性疲劳综合症是一种使许多美国人致残的疾病，最近被认为与一种新的人类逆转录病毒的存在有关。我们将调查这种逆转录病毒是否对疾病的发展既必要又充分，或者是否涉及其他病原体。我们将确定慢性疲劳综合征的健康和运动不耐受程度是否与特定的病毒变异、病毒蛋白表达和/或免疫系统功能障碍有关。

DESCRIPTION (provided by applicant): Chronic fatigue syndrome (CFS) is an illness characterized by long-term fatigue, impaired memory or concentration, sore throat, tender lymph nodes, muscle pain, multi-joint pain, new headaches, unrefreshing sleep, and exercise intolerance. While the cause(s) of chronic fatigue syndrome has not been established definitively, a number of outbreaks implicate an infectious etiology. A variety of pathogens have been reported in individual CFS patients or found more frequently in CFS patients than controls, including various types of viruses. The immune systems of CFS patients exhibit both chronic activation and dysfunction. Recently, a new human retrovirus named XMRV (Xenotropic Murine Leukemia Virus-Related Virus) has been detected in a large proportion of CFS patients tested, but in only 4% of healthy subjects. We plan to learn more about the association of XMRV and other pathogens with CFS by examining an outbreak cohort not previously screened for the presence of XMRV. Other viruses, microbes, and parasites that may be associated with XMRV will also be detected with the use of a panmicrobial DNA microarray. We will determine whether the presence of XMRV and/or other pathogens is related to the current state of health of individuals who became ill during a 1985 outbreak in rural New York. Assuming that most members of the New York cohort are infected with XMRV, we will amplify and sequence XMRV envelope genes derived from blood cells of 40 individuals who became ill as children in 1985. We will also sequence envelope genes from 80 subjects in the Nevada cohort known to exhibit a high degree of XMRV infection. We will examine phylogenetic relationships between the Nevada and New York XMRV variants and will observe whether any amino acid substitutions correlate with the current state of health of the subjects. We will also study the possible association of XMRV and XMRV protein expression in the phenomenon of exercise intolerance. We will examine XMRV-infected CFS patients before and after an exacerbation of symptoms caused by serial exercise testing. We will determine whether increases in inflammatory cytokines, a growth factor, and nitric oxide, or blood cell changes are correlated with the extent of reduced physical ability that can be measured during a second exercise test taken after induction of postexertional malaise. All of these experiments will be designed to assess whether particular XMRV sequences and expression levels play a role in the symptoms experienced by CFS patients and to detect possible underlying mechanisms of the disability that impairs their physical activity. PUBLIC HEALTH RELEVANCE: Chronic fatigue syndrome, an illness that disables many Americans, has recently been associated with the presence of a new human retrovirus. We will investigate whether this retrovirus is both necessary and sufficient for the development of the illness, or whether additional pathogens are involved. We will determine whether the level of health and exercise intolerance in chronic fatigue syndrome is related to particular virus variants, expression of viral proteins, and/or dysfunction of the immune system.