CCR5 and CXCR4 Binding Chemokines and Oral HIV Infection

说明(申请人提供)：口腔接触艾滋病毒-1是发展中国家儿童艾滋病毒-1感染的主要原因，在这些国家，由于文化和社会经济原因，大多数感染艾滋病毒-1的妇女以母乳喂养婴儿。确定保护婴儿免受艾滋病毒-1感染的因素可能会导致开发新的药物，在这些环境中防止艾滋病毒-1母婴传播。趋化因子是HIV-1共同受体CCR5和CXCR4的天然配体，是潜在的候选者。体外研究表明，CCR5和CXCR4结合的趋化因子通过受体阻断或下调抑制HIV-1。临床研究和描述与这些趋化因子相关的基因突变的研究也支持趋化因子在HIV-1感染和疾病进展中的作用。这项拟议研究的目的是确定CC和CXC趋化因子(MIP-1、MIP-1、RANTES和SDF-1)是否对产中和母乳中的HIV-1传播具有保护作用。这项拟议的研究将利用在内罗毕进行的一项由美国国立卫生研究院资助的为期5年的围产期研究的基础设施，该研究名为“CTL和预防母乳HIV-1传播”研究。队列中的母乳样本将被用来确定在12个月的随访中，用酶联免疫吸附试验测量的趋化因子水平与婴儿感染艾滋病毒-1的风险之间的关系。母乳趋化因子水平也将与HIV-1病毒载量和母体SDF-1、RANTES和CCR5辅助受体的基因型有关。将在内罗毕招募50名感染艾滋病毒-1的孕妇和25名未感染艾滋病毒-1的孕妇，以收集更多的样本(产妇血液、母乳、宫颈阴道液、婴儿脐带血、婴儿唾液)，以便更详细地描述趋化因子的产生。这个队列的目的将是通过细胞内趋化因子染色来识别那些负责局部产生趋化因子的细胞，并确定不同隔室中趋化因子水平之间的关系。通过内罗毕、牛津和西雅图科学家的合作和专业知识，这项拟议的研究将为如何利用趋化因子和趋化因子类似物开发创新疗法来预防婴儿HIV-1感染提供洞察力。

DESCRIPTION (provided by applicant): Oral exposure to HIV-1 accounts for the majority of pediatric HIV-1 infections in developing countries where most HIV-1 infected women breastfeed their babies for cultural and socioeconomic reasons. Identifying factors that protect infants against HIV-1 infection may lead to the development of novel agents to prevent mother-to-child HIV-1 transmission in these settings. Chemokines, the natural ligands for the HIV-1 co-receptors CCR5 and CXCR4, are potential candidates. In vitro studies have demonstrated that CCR5 and CXCR4 binding chemokines inhibit HIV-1 by receptor blockade or downregulation. Clinical studies and studies describing genetic mutations associated with these chemokines also support a role for chemokines in HIV-1 infection and disease progression. The goal of the proposed study is to determine whether the CC and CXC chemokines (MIP-1?, MIP-1?, RANTES, and SDF-1) protect against intrapartum and breastmilk HIV-1 transmission. The proposed study will utilize the infrastructure of an ongoing 5 year NIH-funded perinatal study in Nairobi, the "CTLs and Prevention of Breastmilk HIV-1 Transmission" study. Breastmilk samples from the cohort will be used to determine the association between chemokine levels measured using ELISA and risk of infant HIV-1 infection during 12 months of follow-up. Breastmilk chemokine levels will also be associated with HIV-1 viral load and maternal genotypes for SDF-1, RANTES, and the CCR5 coreceptor. A new cohort of 50 HIV-1 infected and 25 HIV-1 uninfected pregnant women in Nairobi will be recruited to collect additional specimens (maternal blood, breastmilk, cervicovaginal fluid, infant cord blood, infant saliva) in order to characterize chemokine production in more detail. The purpose of this cohort will be to identify those cells responsible for local production of chemokines using intracellular chemokine staining and to define the relationship between chemokine levels in different compartments. Through the collaboration and expertise of scientists in Nairobi, Oxford, and Seattle, the proposed study will provide insight into how chemokines and chemokine analogs may be used to develop innovative therapies to prevent infant HIV-1 infection.