Vertical CMV transmission in the setting of maternal HIV-1 infection in Kenya

描述(申请人提供)：候选人：詹妮弗·斯莱克博士，博士，华盛顿大学过敏和传染病系高级研究员。Slyker博士提议设立K01职业发展奖，以获得流行病学和临床研究方面的指导，再加上她在免疫学方面的严谨背景，这将使她能够在分子流行病学领域追求长期的职业生涯，重点关注感染艾滋病毒的妇女和儿童。在获奖期间，斯莱克博士将接受在流行病学、生物统计学、临床试验和巨细胞病毒研究方面由在这些领域拥有相当专业知识的导师(John-Stewart、Richardson和Boeckh博士)提供的培训，这些导师都致力于提供深入的支持，并拥有丰富的导师经验。随着CMV疫苗和治疗方法的不断发展，拟议的研究解决了一个具有高度公共卫生意义的主题，具有重要的潜在影响。该研究计划将培养斯莱克博士在复杂分析、研究设计和CMV发病机制方面的技能。候选人和研究计划预计将导致斯莱克博士发展成为一名独立的研究科学家。华盛顿大学将为Slyker博士的职业发展提供一个理想的环境，获得有助于她长期成功的资源和机会。此外，Slyker博士与肯尼亚儿科科学家的持续合作将为未来相关研究的设计提供背景。 研究：有证据表明，巨细胞病毒(CMV)感染对HIV-1感染婴儿的发病率和死亡率有显著影响。一些新的进展为在资源有限的情况下改进CMV的诊断、治疗和预防带来了希望。这些措施包括从干燥的血斑进行CMV诊断，降低毒性的新型抗CMV药物，以及开发CMV疫苗的进展。对于这项K-应用，Slyker博士将使用肯尼亚3个随机对照试验的数据和样本进行研究，这些试验包括感染艾滋病毒的妇女及其婴儿。CMV病毒载量将从三项试验的储存样本中测量。本研究的目的是：1)确定母乳喂养对婴儿巨细胞病毒感染的影响。将对随机接受母乳喂养的婴儿和配方奶喂养的婴儿进行CMV时间的比较。2)评价母体HAART对母乳CMV病毒载量和垂直传播的影响。母乳CMV病毒载量将在产后第一年在随机接受ZDV/NVP和HAART的HIV感染妇女之间进行连续时间点的比较。3)评价孕期和哺乳期应用万乃洛韦治疗对减少母体CMV复制和传播的效果。将比较服用万乃洛韦和安慰剂的HIV感染妇女所生婴儿的巨细胞病毒感染时间。这一补充研究将提供有关艾滋病毒-1背景下巨细胞病毒流行病学的重要新数据，并将为可能降低婴儿发病率和死亡率的新干预措施奠定基础。 与公共卫生相关：詹妮弗·斯莱克博士是华盛顿大学过敏和传染病部门的高级研究员。对于K01奖项，职业发展计划和拟议的研究将带来分析挑战和机会，并将与流行病学、统计分析、临床试验设计和CMV病毒学方面的指导相结合，使候选人能够在分子流行病学方面发展独立的研究生涯。这些研究结果将是设计阻断巨细胞病毒垂直传播干预措施的核心，这是一项旨在降低艾滋病毒感染婴儿发病率和死亡率的战略。

DESCRIPTION (provided by applicant): Candidate: Dr. Jennifer Slyker, PhD, is a Senior Fellow in the Division of Allergy and Infectious Diseases at the University of Washington. Dr. Slyker proposes a K01 Career Development Award to gain mentorship in epidemiology and clinical research which, combined with her rigorous background in immunology, will enable her to pursue a long-term career in molecular epidemiology focusing on women and children at risk for HIV. During the award period, Dr. Slyker will receive training in epidemiology, biostatistics, clinical trials, and CMV research by mentors with considerable expertise in these areas (Drs. John-Stewart, Richardson, Boeckh), all of whom are committed to provide intensive support and have extensive mentorship experience. The proposed research addresses a topic of high public health significance with important potential implications as CMV vaccines and treatments continue to evolve. The research plan will foster opportunities for Dr. Slyker to gain skills in complex analyses, study design and CMV pathogenesis. The candidate and research plan is anticipated to result in Dr. Slyker's development into an independent research scientist. The UW will provide an ideal milieu for Dr. Slyker's career development with access to resources and opportunities that will foster her long-term success. In addition, Dr. Slyker's continued collaboration with Kenyan pediatrician scientists will provide a context for the design of relevant future studies. Research: There is evidence that cytomegalovirus (CMV) infection contributes significantly to morbidity and mortality in HIV-1 infected infants. Several new advances offer hope for improved diagnosis, treatment and prevention of CMV in resource-limited settings. These include CMV diagnosis from dried blood spots, novel anti-CMV drugs with reduced toxicity, and progress toward the development of a CMV vaccine. For this K-application Dr. Slyker will conduct research using a repository of data and specimens from 3 Kenyan randomized controlled trials comprising HIV-infected women and their infants. CMV viral loads will be measured from stored specimens from the three trials. The aims of the study are 1) To determine the influence of breastfeeding on infant CMV acquisition. Time to CMV will be compared between infants randomized to breastfeeding versus formula feeding. 2) To evaluate the impact of maternal HAART on breast milk CMV viral load and vertical CMV transmission. Breast milk CMV viral loads will be compared at serial time-points during the first year post-partum between HIV-infected women randomized to ZDV/NVP versus HAART. 3) To evaluate the efficacy of maternal valacyclovir therapy during pregnancy and breastfeeding to reduce maternal CMV replication and CMV transmission. Time to CMV will be compared between infants born to HIV-infected women randomized to valacyclovir versus placebo. This complement of studies will provide important new data on the epidemiology of CMV in the setting of HIV-1 and will form a foundation for new interventions that may decrease infant morbidity and mortality. Public Health Relevance: Jennifer Slyker, PhD is a Senior Fellow in the Division of Allergy and Infectious Diseases at the University of Washington. For this K01 award, the career development plan and proposed research studies will pose analytical challenges and opportunities which will be combined with mentorship in epidemiology, statistical analyses, clinical trials design, and CMV virology which will enable the candidate to develop an independent research career in molecular epidemiology. The research findings will be central to the design of interventions to interrupt vertical cytomegalovirus transmission, a strategy aimed at reducing morbidity and mortality in HIV- infected infants.