Innate antiviral factors in breast milk and the oral HIV-1 reservoir

母乳和口腔 HIV-1 储存库中的先天抗病毒因子

基本信息

批准号：
8974201
负责人：
Sallie R. Permar
金额：
$ 59.48万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-03 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8974201
关键词：
Abate Acute Adherence Anti-Inflammatory Agents Anti-Retroviral Agents Anti-inflammatory Antiviral Agents Area Avidity Binding Binding Sites Breast Feeding C-terminal CD4 Positive T Lymphocytes Cell Death Cells Childhood Chronic Development Disease remission Dose Ensure Environment Epidemic Epithelial Cells Epitopes Extracellular Matrix Proteins Fibrinogen Glycoproteins Growth HIV HIV-1 Human Milk In Vitro Infant Infection Infection prevention Inflammatory Knowledge Life Liposomes Lymphoid Tissue Macaca mulatta Mediating Milk Milk Proteins Modeling Mothers Neonatal Oral Oral cavity Plague Prevalence Prevention strategy Property Prophylactic treatment Proteins Research Role Route Safety Tenascin Tonsil Tonsillar Tissue Toxic effect Viral Virus Work Working Women antimicrobial base cytokine design improved in vivo Model inhibitor/antagonist novel oral infection oral tissue public health relevance scale up simian human immunodeficiency virus transmission process

项目摘要

DESCRIPTION (provided by applicant): Over a quarter million (>250,000) infants continue to become infected with HIV-1 annually, despite widespread availability of maternal-infant antiretroviral (ARV) prophylaxis. Approximately half of these infant HIV-1 infections occur via breastfeeding, a mainstay of infant growth and survival in developing regions. Therefore, designing safe strategies to further reduce breast milk HIV-1 transmission is crucial to ending the global pediatric HIV-1 epidemic. The oral cavity is a unique environment for establishment of HIV-1 infection and the associated pyroptotic cell death of CD4+ T cells in lymphoid tissues, such as the tonsils. Blocking the establishment of the oral HIV-1 reservoir and subsequent systemic spread in infants is key to interrupting HIV-1 acquisition and limiting the size of the initial virus reservoir, which may be required to achieve infant HIV-1 "remission" or "cure". Remarkably, despite chronic, daily mucosal virus exposure for up to two years of life, the majority (~90%) of HIV-1-exposed breastfeeding In fact, several breast milk factors with innate HIV-1 inhibitory activity have been identified, including our recently discovery of the HIV-1-neutralizing protein Tenascin-C (TNC). infants are protected against HIV-1 acquisition, suggesting that there are protective factors in breast milk that may block establishment of the HIV-1 reservoir. However, there is a gap in our understanding of how these innate HIV-1 inhibitors in breast milk impact establishment of the oral HIV-1 reservoir and the pyroptotic spread of HIV-1 in oral lymphoid tissues. We hypothesize that innate anti-viral and anti-inflammatory factors in breast milk work in concert to block establishment of the HIV-1 reservoir and reduce the subsequent pryoptotic cell death of CD4+ T cells in oral lymphoid tissues. In this proposal, we aim to define the impact of innate factors in breast milk on the establishment of the oral HIV-1 reservoir, HIV-1-induced pyroptotic cell death, and systemic viral spread from oral lymphoid tissues. Moreover, we will attempt to harness the innate anti-HIV-1 properties of breast milk by producing a more potent, multimeric derivative of TNC's active domain and investigate its ability to limit the oral HIV-1 reservoir and the virus-induced pyroptotic cell deah. Defining the basis of the natural protection provided by breast milk against establishment of the oral HIV-1 reservoir in the majority of HIV- exposed infants is crucial to the development of safe, nontoxic strategies to improve HIV-1-free survival for breastfeeding infants globally.

描述（由适用提供）：超过25万（> 250,000）的婴儿每年继续感染HIV-1，期望的宽度可用性可用性，可供您预防产妇抗逆转录病毒（ARV）。这些婴儿HIV-1感染中大约有一半是通过母乳喂养发生的，这是婴儿生长的主要和发育区的存活。因此，设计安全的策略以进一步减少母乳HIV-1传播对于结束全球小儿HIV-1流行至关重要。口腔是建立HIV-1感染和淋巴组织中CD4+ T细胞的相关凋亡细胞死亡（例如扁桃体）的独特环境。阻止口服HIV-1储层的建立并随后在婴儿中的全身性扩散是中断HIV-1采集并限制初始病毒储量的大小，这可能是实现婴儿HIV-1“缓解”或“治疗”的关键。值得注意的是，尽管每天长期暴露了长达两年的寿命，但实际上，大多数HIV-1暴露母乳喂养的大多数（〜90％），但已经确定了几种具有先天HIV-1抑制活性的母乳因素，包括我们最近发现的HIV-1中性化蛋白质蛋白质Tenascin-C（TNC）。婴儿受到保护，免受HIV-1的获取，表明母乳中有受保护的因素可能阻止HIV-1储层的建立。但是，我们对母乳中这些先天性HIV-1抑制剂的理解存在差距，这会影响口服HIV-1储存剂的建立以及HIV-1在口腔淋巴组织中的凋亡扩散。我们假设母乳中的先天抗病毒和抗炎因子协同工作，以阻止HIV-1储层的建立，并减少口服淋巴组织中CD4+ T细胞的随后促毒细胞死亡。在此提案中，我们的目的是定义先天因素对母乳的影响对建立口服HIV-1储层，HIV-1诱导的凋亡细胞死亡以及从口服淋巴组织中的全身病毒传播。此外，我们将尝试通过产生更多潜在的TNC活性结构域的多媒体衍生物来利用母乳的先天抗HIV-1特性，并研究其限制口服HIV-1储层和病毒诱导的凋亡细胞DEAH的能力。定义母乳免于在大多数艾滋病毒暴露婴儿中建立口服HIV-1水库提供的自然保护的基础无毒的策略可改善全球母乳喂养婴儿的无HIV-1生存期。