CCR5 and CXCR4 Binding Chemokines and Oral HIV Infection

CCR5 和 CXCR4 结合趋化因子与口腔 HIV 感染

• 批准号: 6552856
• 负责人: Grace John-Stewart
• 金额: $ 29.41万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-15 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6552856
• 关键词: Africa; Europe; HIV infections; breast feeding; chemokine; clinical research; enzyme linked immunosorbent assay; epidemiology; gene mutation; genotype; histocompatibility typing; human pregnant subject; infant human (0-1 year); oral health; patient oriented research; polymerase chain reaction; receptor binding; receptor expression; vertical transmission; virus load

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.

描述（由申请人提供）：口服暴露于HIV-1是发展中国家儿童HIV-1感染的主要原因，因为文化和社会经济原因，大多数HIV-1感染妇女母乳喂养婴儿。确定保护婴儿免受HIV-1感染的因素可能会导致开发新的药物来预防这些环境中的母婴HIV-1传播。趋化因子是HIV-1共受体CCR 5和CXCR 4的天然配体，是潜在的候选者。体外研究表明，CCR 5和CXCR 4结合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。本研究的目的是确定CC和CXC趋化因子（MIP-1？，MIP-1？，RANTES和SDF-1）防止分娩期和母乳中的HIV-1传播。拟议的研究将利用在内罗毕进行的为期5年的NIH资助的围产期研究的基础设施，即“CTL和母乳HIV-1传播的预防”研究。来自队列的母乳样本将用于确定在12个月随访期间使用ELISA测量的趋化因子水平与婴儿HIV-1感染风险之间的关联。母乳趋化因子水平也与HIV-1病毒载量和母亲SDF-1、RANTES和CCR 5辅助受体的基因型相关。将在内罗毕招募50名HIV-1感染和25名HIV-1未感染孕妇的新队列，以收集更多样本（母亲血液、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产生的特征。该队列的目的是使用细胞内趋化因子染色鉴定负责局部产生趋化因子的那些细胞，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，拟议的研究将深入了解趋化因子和趋化因子类似物如何用于开发预防婴儿HIV-1感染的创新疗法。