Immune correlates of tuberculosis and non-tuberculosis infectious morbidity in Southern African HIV-exposed, uninfected infants.

项目总结/摘要 感染艾滋病毒的妇女所生的100多万婴儿免于纵向感染艾滋病毒。这个公共 保健方面的成功归功于扩大孕产妇抗逆转录病毒治疗，目前世界卫生组织 世卫组织（世卫组织）的政策建议艾滋病毒感染者，包括孕妇，终生接受抗逆转录病毒治疗 妇女然而，在资源有限的环境中，艾滋病毒暴露的未感染婴儿（HEU）的经验是2至4倍， 与同一地区未接触艾滋病毒（HU）的婴儿相比， 设置.这主要是由于疟疾和呼吸道疾病，包括肺结核。HEU 儿童潜伏性结核感染（LTBI）的发病率也比艾滋病毒高20倍， 未暴露（HU）儿童。几项研究描述了高浓缩铀儿童的免疫异常， 也许可以部分解释高浓缩铀婴儿的脆弱性。在博茨瓦纳和南非， 结核病和艾滋病毒流行，出生时卡介苗免疫率超过98%。虽然一些 研究表明，接种卡介苗可预防HU婴儿的结核性脑膜炎和播散性结核病 并可能具有超出结核病保护范围的异源效应， 免疫力可能会影响卡介苗在直接预防结核病和提供 非特异性免疫保护。利用现有的两个前瞻性观察母婴健康 博茨瓦纳和南非正在分别进行研究，这两个国家都在跟踪高浓缩铀和高浓缩铀 我们将使用900名婴儿（600名高浓缩铀婴儿）的数据和标本， 使用免疫学研究评价BCG疫苗诱导的特异性和非特异性免疫应答 评估BCG疫苗保护的相关性。具体而言，我们将1）定义TB相关和TB- BCG接种的HEU和HU婴儿的发病率和死亡率的独立原因; 2）定义 使用多色流式细胞术检测高浓铀婴儿结核感染免疫相关性， 比较常规和非常规T细胞对BCG疫苗接种的反应; 3）探索HIV的影响 暴露于BCG诱导的外周血单核细胞。我们预计，研究结果将告知结核病 为高浓缩铀婴儿开发疫苗，并可能确定进一步的潜在干预措施， 这一脆弱的婴儿群体更经常地经历传染病发病率和死亡率。

PROJECT SUMMARY/ABSTRACT Over one million infants born to women living with HIV are spared from vertical HIV acquisition. This public health success is attributable to scaling up of maternal antiretroviral treatment (ART), with current World Health Organization (WHO) policies recommending lifetime ART for persons living with HIV, including pregnant women. Yet, HIV-exposed uninfected (HEU) infants in resource-constrained settings experience 2- to 4-fold higher infectious cause morbidity and mortality compared with HIV-unexposed (HU) infants in the same settings. This is primarily due to diarrheal disease and respiratory illness, including tuberculosis (TB). HEU children also experience 20-fold increased incidence of latent TB infection (LTBI) compared with HIV- unexposed (HU) children. Several studies have described immune abnormalities among HEU children, which might explain a portion of HEU infant vulnerability. In both Botswana and South Africa, also settings with high TB and HIV prevalence, bacille Calmette-Guérin (BCG) immunization rates at birth exceed 98%. While some studies have shown that BCG vaccination protects against TB meningitis and disseminated TB in HU infants and may have heterologous effects that extend beyond TB protection, the reported alterations in HEU infant immunity may impact the efficacy of the BCG vaccine both in directly protecting against TB and in providing the non-specific immune protection. Leveraging two existing prospective observational maternal-child health studies underway in Botswana and South Africa, respectively, each of which is following both HEU and HU infants from birth and beyond infancy, we will use data and specimens from 900 infants (600 HEU infants) to evaluate BCG vaccine-induced specific and non-specific immune responses while using immunological studies to assess correlates of BCG vaccine protection. Specifically, we will 1) Define TB-related and TB- independent causes of morbidity and mortality in BCG vaccinated HEU and HU infants; 2) Define immune correlates of risk for tuberculosis infection in HEU infants using polychromatic flow cytometry to compare conventional and unconventional T-cell responses to BCG vaccination; 3) Explore the effect of HIV exposure on BCG-induced peripheral blood monocytes. We anticipate that study findings will inform TB vaccine development for HEU infants,and might identify further potential interventions to protect against infectious morbidity and mortality more frequently experienced by this vulnerable population of infants.