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

描述（由申请人提供）：隐球菌性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%，在资源有限的国家死亡率为20-90%。隐球菌病可以作为潜伏感染存在，在出现症状前21天隐球菌抗原（CrAg）平均呈阳性，尽管一些研究表明潜伏期可达数年。最近的研究发现，在非洲和亚洲CD4-/<100细胞/mm3的无症状艾滋病患者中，CrAg+的患病率为8-18%。CrAg+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。在美国的hiv感染患者中没有发现无症状的CrAg+。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，建议开发一种小鼠潜伏性隐球菌病模型。

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.