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

美国 HIV 感染者的无症状隐球菌抗原血症

• 批准号: 8618259
• 负责人: Michele W Tang
• 金额: $ 6.65万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-05 至 2014-04-03
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8618259
• 关键词: AIDS clinical trial group; AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Africa; Antibodies; Antigens; Asia; Biological Assay; Blood; CD4 Lymphocyte Count; Cells; Chronic; Clinical; Cryptococcal Meningitis; Cryptococcus neoformans infection; Data; Development; Disease; Disease Management; Enrollment; Exposure to; Fluconazole; Geographic Distribution; Guidelines; HIV; HIV Infections; Immune; Immune System Diseases; Immunologics; Immunosuppression; Individual; Infection; Inflammatory; Investigation; Lateral; Lead; Lifting; Lung; Mediating; Modeling; Monitor; Mus; Mycoses; Natural History; Nose; Opportunistic Infections; Organ; Outcome; Participant; Pathogenesis; Patients; Plasma; Prevalence; Research; Research Design; Resolution; Resources; Risk; Risk Factors; Sampling; Serum; Symptoms; Syndrome; Systemic infection; Time; United States; Urine; Viral Load result; Viral load measurement; Whole Blood; antiretroviral therapy; base; burden of illness; follow-up; immune function; immunosuppressed; insight; latent infection; mortality; mouse model; prevent; public health relevance; reconstitution; response; restoration; screening; tool; trend

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.

隐球菌脑膜炎是艾滋病患者的一种毁灭性疾病，在美国死亡率为12%，在资源有限的环境中死亡率为20-90%。隐球菌病可以作为潜伏感染存在，在症状出现前平均隐球菌抗原（CrAg）阳性21天，尽管一些研究表明潜伏期长达数年。最近的研究发现，在非洲和亚洲的无症状艾滋病患者中，CD 4-/<100个细胞/mm 3的CrAg+患病率为8-18%。CrAg+可预测有症状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增加相关。在美国，无症状CrAg+尚未在HIV感染患者中得到表征。本研究旨在确定美国无症状CrAg+的患病率和自然史。为了进一步研究潜伏性隐球菌病和免疫介导的再激活风险，建议建立潜伏性隐球菌病的小鼠模型。 目的：1）确定美国CD 4 < 200 cells/mm 3的AIDS患者中无症状CrAg的患病率，并描述与症状性隐球菌病发展相关的风险因素。2)建立潜伏性隐球菌感染的小鼠模型，并使用CrAg滴度监测疾病活动性，量化免疫抑制和随后免疫功能恢复的疾病负担。 研究设计：在目标1中，在美国登记的CD 4 < 200个细胞/mm 3的无症状HIV患者的储存血浆样品。基于ACTG的研究将筛查CrAg以确定患病率。为了评估发生疾病的风险因素，将比较发生和未发生隐球菌病的基线CrAg阳性受试者的连续CrAg滴度、CD 4、VL、抗逆转录病毒治疗时间和氟康唑使用情况。目的2：通过吸入感染隐球菌，建立隐球菌潜伏感染小鼠模型。新生儿建立持续的低水平感染。潜伏感染的小鼠将用抗CD 4抗体进行免疫抑制，其中一组小鼠经历持续的CD 4耗竭，而另一组将解除免疫抑制。将对两组进行随访，以了解疾病的重新激活、持续或自发消退。将在全血、血清和尿液中进行系列定量CrAg侧向流测定（LFA），并与小鼠器官中的真菌负荷相关。 意义：这项研究将首次描述无症状隐球菌病， 这是为美国CrAg+ HIV/AIDS患者制定适当治疗指南的必要步骤。发展一种小鼠模型，允许操作的免疫状态将有助于更好地了解艾滋病患者的疾病，并提供了一个有价值的工具，为进一步研究的发病机制和疾病的管理。