CMV Dynamics and Transmission Among Pregnant Women Living with HIV

项目摘要 巨细胞病毒（CMV）是全球领先的先天性感染，导致巨大的 儿童听力损失和神经发育迟缓的负担。两千万女性 全球范围内的HIV（WLWH）比没有HIV的女性更有可能进行活跃的CMV复制 更有可能将巨细胞病毒传播给每年出生的130万艾滋病毒暴露婴儿。结合 全基因组血清学和病毒学分析，该项目将使用现有的样本，以新的工具， 描述妊娠期间CMV再感染和脱落的特征。我们还将探讨具体的 导致母体再感染和先天性或出生后婴儿感染的菌株之间的基因型。 利用329名WLWH及其子女的现有纵向样本（在 怀孕，分娩，直到产后6周），我们将致力于以下具体目标： 1)使用新的血清学方法估计WLWH妊娠期间CMV再感染的频率 方法. 2)确定再感染和特定病毒株的CMV复制之间的关联， 怀孕在WLWH。 3)确定与传播给孕妇或其子女相关的基因型特征。 将使用传统的CMV株特异性抗体和新的CMV株特异性抗体进行血清学分析。 VirScan技术。VirScan允许使用噬菌体展示文库进行全面的血清学分析 我们已经适应了能够识别所有（> 10，000）测序CMV的所有抗体， 菌株/变体。将通过定量PCR对母婴唾液进行CMV脱落测定 以及母亲的血液和阴道拭子。将对PCR阳性进行CMV基因组分析 使用下一代测序技术与机器学习相结合的样本。菌株 将对孕妇中存在的病毒进行定性，并对传播给婴儿的病毒进行测序。 区分传播病毒和非传播病毒的基因单核苷酸多态性 具有潜在的功能意义。统计分析将评估 CMV/HIV参数与关注的结局（包括孕产妇再感染）之间的关系， 先天性/产后感染。 从该项目中获得的知识可能会导致预防性建议， 基于新阐明的WLWH特异性风险因素的孕产妇再感染， 怀孕期间的再感染和预防先天性感染。最后，这可能有助于减少 CMV感染对受艾滋病毒影响的家庭造成的巨大负担， 基因型导致CMV传播，因此应包括在候选疫苗中。

PROJECT SUMMARY Cytomegalovirus (CMV) is the leading congenital infection globally, resulting in an enormous burden of childhood hearing loss and neurodevelopmental delay. The 20 million women living with HIV (WLWH) worldwide are more likely to have active CMV replication than women without HIV and are more likely to transmit CMV to the 1.3 million HIV-exposed infants born annually. Combining genome-wide serologic and virologic analyses, this project will use existing samples to new tools to characterize CMV reinfection and shedding during pregnancy. We will also explore the role of specific genotypes among strains causing maternal reinfection and congenital or postnatal infant infections. Leveraging existing longitudinal samples from 329 WLWH and their children (collected during pregnancy, at delivery, and until 6 weeks postpartum), we will address the following specific aims: 1) Estimate the frequency of CMV reinfection during pregnancy among WLWH using novel serologic methods. 2) Determine the association between reinfection and CMV replication of specific viral strains during pregnancy in WLWH. 3) Identify genotypic features associated with transmission to pregnant women or their children. Serological profiling will be done using traditional CMV strain-specific antibodies and novel VirScan technology. VirScan allows comprehensive serological profiling using a phage display library that we have adapted to be able to identify all antibodies to all (>10,000) sequenced CMV strains/variants. CMV shedding will be determined by quantitative PCR on maternal & infant saliva and maternal blood & vaginal swabs. CMV genomic analyses will be conducted on PCR positive samples using next-generation sequencing techniques combined with machine learning. The strains present in pregnant women will be characterized and those transmitted to infants will be sequenced. Single nucleotide polymorphisms in genes that distinguish transmitted from non-transmitted viruses with potential functional significance will be identified. Statistical analyses will evaluate associations between CMV/HIV parameters and outcomes of interest including maternal reinfection and congenital/postnatal infection. The knowledge gained from this project may result in preventative recommendations for maternal reinfections based on newly elucidated risk factors specific to WLWH, treatment for reinfection during pregnancy, and prevention of congenital infection. Finally, this may help to reduce the enormous burden of CMV infection on families affected by HIV, by informing which CMV genotypes result in CMV transmission and should therefore be included in candidate vaccines.