Asymptomatic Cryptococcal Antigenemia in HIV-Infected Patients in the United Stat

描述(申请人提供)：隐球菌性脑膜炎是艾滋病患者的一种破坏性疾病，在美国死亡率为12%，在资源有限的情况下死亡率为20%-90%。隐球菌病可作为一种潜伏感染存在，平均隐球菌抗原(CRAG)阳性在症状出现前21天，尽管一些研究表明有证据表明潜伏数年。最近的研究发现，在非洲和亚洲的无症状艾滋病患者中，CD4-/&lt；100细胞/mm3的CRAG+流行率为8%-18%。CRIG+可预测有症状的隐球菌病的发展和随后的死亡率，而氟康唑的使用与生存率的增加有关。在美国，无症状的CRIG+并不是HIV感染患者的特征。这项研究旨在确定美国无症状CRAG+的患病率和自然病史。为了进一步研究隐匿性隐球菌病和免疫介导的再激活风险，建议建立一种隐匿性隐球菌病小鼠模型。 目的：1)确定美国CD4&lt；200细胞/mm~3的艾滋病患者中无症状CRAG的患病率，并描述与有症状的隐球菌病发生有关的危险因素。2)建立隐球菌潜伏感染的小鼠模型，用CRIG滴度监测疾病活动性，量化疾病负担，免疫抑制和随后的免疫功能恢复。 研究设计：在目标1中，在美国的ACTG研究中，将对CD4&lt；200细胞/mm3的无症状HIV患者的储存血浆样本进行CRAG筛查，以确定患病率。为了评估发生疾病的危险因素，基线CRAG阳性、有和没有发生隐球菌疾病的受试者将与系列CRAG滴度、CD4、VL、抗逆转录病毒治疗的时机和氟康唑的使用情况进行比较。在目标2中，将通过吸入感染新生隐球菌来建立潜伏的隐球菌感染的小鼠模型，以建立持续的、低水平的感染。潜伏感染的小鼠将用抗CD4抗体进行免疫抑制，其中一组小鼠遭受持续的CD4耗竭，而另一组小鼠的免疫抑制将被解除。两组患者都将接受复活、持续治疗或疾病自然缓解的治疗。随后将在全血、血清和尿液中进行一系列定量岩层侧向流动分析(LFA)，并与小鼠器官中的真菌负荷相关联。 这项研究将首次描述无症状的隐球菌病。 这是为美国CRAG阳性艾滋病毒/艾滋病患者制定适当治疗指南的必要步骤。建立一种可以操纵免疫状态的小鼠模型将有助于更好地了解艾滋病患者的疾病，并为进一步研究发病机制和疾病管理提供有价值的工具。 公共卫生相关性：来自亚洲和非洲的最新研究表明，对无症状、严重免疫抑制的艾滋病毒感染者进行隐球菌抗原(CRAG)筛查，并对CRAG阳性的人进行治疗，可以防止发生毁灭性的真菌感染。我们建议使用艾滋病临床试验小组研究的储存血清样本来确定美国无症状隐球菌感染的流行率、地理分布和进展的危险因素。我们还建议建立一种隐球菌潜伏感染的小鼠模型，以更好地了解发生活动性疾病的免疫触发因素，并更好地表征具有真菌疾病负担的岩滴度。这些研究将有助于进一步了解潜在的隐球菌疾病，并为美国和全球对无症状疾病的最佳管理提供信息。

DESCRIPTION (provided by applicant): Cryptococcal meningitis is a devastating disease in AIDS patients, with a mortality of 12% in the U.S. and 20-90% in resource-limited settings. Cryptococcosis can exist as a latent infection with an average cryptococcal antigen (CrAg) positivity of 21 days prior to development of symptoms, although some studies suggest evidence of latency for years. Recent research found an 8-18% prevalence of CrAg+ in asymptomatic AIDS patients in Africa and Asia with CD4-/<100 cells/mm3. CrAg+ predicted development of symptomatic cryptococcal disease and subsequent mortality, while fluconazole use was associated with increased survival. Asymptomatic CrAg+ has not been characterized in HIV-infected patients in the United States. This study seeks to determine the prevalence and natural history of asymptomatic CrAg+ in the United States. For further investigation of latent cryptococcal disease and immune-mediated risks of reactivation, development of a murine model of latent cryptococcal disease is proposed. Aims: 1) To determine the prevalence of asymptomatic CrAg among AIDS patients with CD4< 200 cells/mm3 in the United States, and to characterize the risk factors associated with the development of symptomatic cryptococcal disease. 2) To develop a murine model of latent cryptococcal infection, and use CrAg titers to monitor disease activity and quantify disease burden with immunosuppression and subsequent restoration of immune function. Research Design: In Aim 1, stored plasma samples of asymptomatic HIV patients with CD4 < 200 cells/mm3 enrolled in U.S.-based ACTG studies will be screened for CrAg to determine prevalence. To assess risk factors for developing disease, subjects positive for baseline CrAg who did, and did not develop cryptococcal disease will be compared with respect with serial CrAg titers, CD4, VL, timing of antiretroviral therapy, and fluconazole use. In Aim 2, a murine model of latent cryptococcal infection will be developed by inhalationally infecting mice with C. neoformans to establish persistent, low level infection. Latently infected mice will be immunosuppressed with anti-CD4 antibody, with one group of mice subjected to persistent CD4-depletion, while the other group will have immunosuppression lifted. Both groups will be followed for reactivation, persistence or spontaneous resolution of disease. Serial quantitative CrAg lateral flow assays (LFAs) will be followed in whole blood, serum and urine, and correlated with fungal burden in mouse organs. Implications: This study will provide the first description of asymptomatic cryptococcal disease in the United States, and is a necessary step towards developing appropriate treatment guidelines for CrAg+ HIV/AIDS patients in the United States. Development of a murine model that allows for manipulation of immune status will contribute to a greater understanding of the disease in AIDS patients, and provide a valuable tool for further study of pathogenesis and disease management. PUBLIC HEALTH RELEVANCE: Recent research from Asia and Africa suggests that screening for cryptococcal antigen (CrAg) in asymptomatic, severely immunosuppressed HIV-infected individuals, and treatment of those who are CrAg positive, can prevent development of a devastating fungal infection. We propose using stored serum samples from AIDS Clinical Trial Group studies to determine the prevalence, geographic distribution, and risk factors for progression of asymptomatic cryptococcal infection in the United States. We also propose developing a mouse model of latent cryptococcal infection to better understand the immune triggers of developing active disease, and to better characterize CrAg-titers with fungal disease burden. These studies will lead to further understanding of latent cryptococcal disease, and inform the optimal management of asymptomatic disease in the United States and globally.