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

描述（由申请人提供）：候选人：詹妮弗·斯莱克博士，博士，是华盛顿大学过敏和传染病系的高级研究员。Slyker博士提出了K 01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格背景，这将使她能够在分子流行病学方面从事长期职业，重点关注有艾滋病毒风险的妇女和儿童。在奖励期间，Slyker博士将接受流行病学，生物统计学，临床试验和CMV研究方面的培训，这些领域的导师（John-Stewart，Richardson，Boeckh博士）都致力于提供密集的支持并具有丰富的指导经验。拟议的研究解决了一个具有高度公共卫生意义的主题，随着CMV疫苗和治疗的不断发展，具有重要的潜在影响。该研究计划将为Slyker博士提供获得复杂分析，研究设计和CMV发病机制技能的机会。候选人和研究计划预计将导致博士斯莱克的发展成为一个独立的研究科学家。UW将为Slyker博士的职业发展提供一个理想的环境，并提供资源和机会，以促进她的长期成功。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。一些新的进展为改善资源有限环境中CMV的诊断、治疗和预防带来了希望。这些包括从干血斑诊断CMV，毒性降低的新型抗CMV药物，以及CMV疫苗的开发进展。Slyker博士将使用来自3个肯尼亚随机对照试验的数据和标本库进行研究，这些试验包括艾滋病毒感染的妇女及其婴儿。将从三项试验的储存标本中测量CMV病毒载量。该研究的目的是1）确定母乳喂养对婴儿巨细胞病毒感染的影响。将比较随机接受母乳喂养与配方奶粉喂养的婴儿发生CMV的时间。2)评价母亲HAART对母乳CMV病毒载量和CMV垂直传播的影响。将在产后第一年的连续时间点比较随机接受ZDV/NVP与HAART的HIV感染女性的母乳CMV病毒载量。3)评价妊娠期和哺乳期母体应用伐昔洛韦治疗减少母体CMV复制和传播的疗效。将比较随机接受伐昔洛韦和安慰剂治疗的HIV感染妇女所生婴儿的CMV时间。这一补充研究将提供关于在HIV-1背景下CMV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。 公共卫生相关性：Jennifer Slyker博士是华盛顿大学过敏和传染病系的高级研究员。对于这个K 01奖，职业发展计划和拟议的研究将带来分析的挑战和机会，将与流行病学，统计分析，临床试验设计和CMV病毒学的指导相结合，这将使候选人能够在分子流行病学方面发展独立的研究生涯。研究结果将是设计干预措施以中断垂直巨细胞病毒传播的核心，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.