Early Events and Determinants of Oral SIV Transmission in Infant Nonhuman Primate

非人类灵长类婴儿经口 SIV 传播的早期事件和决定因素

• 批准号: 8732835
• 负责人: CRISTIAN APETREI
• 金额: $ 37.25万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-20 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8732835
• 关键词: Accounting; Acute; African; Animal Model; Animals; Automobile Driving; Autopsy; Biological Assay; Breast Feeding; CCR5 gene; CD4 Positive T Lymphocytes; Cells; Cercopithecus pygerythrus; Chronic; Control Groups; Data; Dissection; Dose; Epithelium; Esophagus; Event; Excision; Exposure to; Genetic Crossing Over; Genome; Goals; HIV; HIV Infections; HIV-1; Health; Human; Human Milk; Immune; Infant; Infection; Inflammation; Intervention; Macaca mulatta; Milk; Modeling; Molecular Cloning; Monitor; Mothers; Mucous Membrane; Natural Resistance; Oral; Oral Administration; Oral mucous membrane structure; Outcome; Permeability; Predisposition; Prevalence; Prevention; Prevention Research; Prevention strategy; Relative (related person); Research; Resistance; Resources; Role; SIV; Safety; Sampling; Site; Stomach; Testing; Time; Tonsil; Translating; Vagina; Viral; Viral Load result; Virus; Virus Diseases; Virus Replication; analytical tool; antiretroviral therapy; base; data reduction; design; human subject; immune activation; in utero; inhibitor/antagonist; innovation; mucosal site; nonhuman primate; novel therapeutic intervention; offspring; oral HIV; prevent; public health relevance; rectal; research study; response; tool; transmission process; virtual; virus host interaction

DESCRIPTION: Oral HIV breastfeeding transmission (BFT) accounts for more than half of the cases of maternal-to-infant HIV transmission (MTIT). In spite of being a priority of HIV-1 research, prevention of oral HIV BFT is difficult to achieve because its mechanisms are not fully understood. Maternal virological and immunological parameters of infection, as well as innate immune factors present in milk, have been associated with oral HIV BFT. These associations are not always evident [i.e., transmission occurs from mothers with low viral loads (VLs) and vice versa, a large proportion of infants remain uninfected in spite of a long-term continuous exposure to high levels of maternal virus], pointing to the involvement of additional factors in transmission. Our preliminary studies showed that in African nonhuman primate (NHP) hosts of SIV: (i) MTIT is virtually nonexistent (<5%) (lower than the levels targeted by the WHO as a goal for achieving "virtual elimination" of HIV-1 MTIT); (ii) low MTIT contrasts with massive offspring SIV exposure both in utero and through BFT due to the high SIV prevalence (>80%) and high acute and chronic VLs in dams; (iii) resistance to SIV BFT is strongly associated with low levels of SIV target cells at mucosal sites of the offspring; (iv) susceptibility to experimental mucosal transmission is proportional to the availability of mucosal CCR5+ CD4+ T cells. Based on these observations, our hypothesis is that the levels of HIV/SIV target cells at the mucosal sites of the breastfed infant drive the efficacy of HIV BFT. To confirm our hypothesis, we identified two NHP models of HIV infection which differ in susceptibility to SIV BFT: (1) SIVmac-infected rhesus macaques (RMs) will serve as a model of effective oral SIV BFT and (2) SIVagm-infected African green monkeys (AGMs) as a model of resistance to oral SIV BFT. By comparing and contrasting these two animal models, we will investigate the mechanism of oral HIV/SIV BFT and explore new strategies to prevent oral HIV transmission. In addition to the use of two animal models in which exposure to breast milk has an opposite outcome, we developed: (1) a new challenge strategy consisting of dose escalation, which we demonstrated in a preliminary study to accurately model natural mucosal transmission, while efficiently infecting the animals; (2) new challenge tools, consisting of transmitted/founder infectious molecular clones (IMCs) that permit us to physiologically model SIV transmission and molecularly tagged IMCs of SIVmac and SIVagm which offer us the advantages of IMCs combined with the possibility to monitor the bottleneck of transmission; (3) a new assay for monitoring virus transmission and the diversity of the transmitted virus (real-time single genome amplification). In a step-wise approach, we will achieve the following Specific aims (SA): SA1. To test the hypothesis that the infant mucosa drives the efficacy of SIV BFT. SA1a. Dissect the relative contribution of milk vs. the levels of infant mucosal target cells in driving HIV-1 BFT. SA1b. Provide proof-of-concept data that reduction of target cell availability in the infant mucosa decreases SIV BFT rates. SA2. To identify the mucosal site of viral entry upon oral HIV/SIV BFT and to assess early mucosal changes that are associated with SIV BFT. SA2a. Perform "virological dissections" of the potential sites of entry. SA2b. Identify the exact site of SIV entry upon oral exposure through breastfeeding and the mucosal factors associated with oral SIV transmission. Relevance. Combined, these studies carried out in NHP species that vary in their susceptibility to SIV BFT, employing innovative interventions and new analytical tools, will delineate the factors responsible for oral SIV BFT and identify new strategies for preventing oral HIV transmission.

描述：口服艾滋病毒母乳传播（BFT）占母婴艾滋病毒传播（MTIT）病例的一半以上。尽管是HIV-1研究的优先事项，但预防口服HIV BFT很难实现，因为其机制尚未完全了解。母体感染的病毒学和免疫学参数以及乳汁中存在的先天免疫因子与口服HIV BFT相关。这些关联并不总是明显的[即，虽然艾滋病毒的传播发生在病毒载量低的母亲，反之亦然，但尽管长期持续暴露于高水平的母体病毒，但很大一部分婴儿仍然未受感染]，这表明传播涉及其他因素。 我们的初步研究表明，在SIV的非洲非人灵长类（NHP）宿主中：（i）MTIT几乎不存在（<5%）（低于世卫组织作为实现“基本消除”艾滋病毒1型母婴传播感染的目标的水平）;（ii）低MTIT与由于高SIV患病率（>80%）而导致的大量子代SIV暴露（子宫内和通过BFT）形成对比和高急性和慢性VL的母鼠;（iii）对SIV BFT的抗性与后代粘膜部位低水平的SIV靶细胞密切相关;（iv）对实验性粘膜传播的易感性与粘膜CCR 5 + CD 4 + T细胞的可用性成正比。基于这些观察结果，我们的假设是，HIV/SIV靶细胞在粘膜部位的水平， 母乳喂养的婴儿驱动艾滋病毒BFT的疗效。 为了证实我们的假设，我们确定了两种HIV感染的NHP模型，它们对SIV BFT的易感性不同：（1）SIVmac感染的恒河猴（RM）将作为有效口服SIV BFT的模型，（2）SIVagm感染的非洲绿色猴（AGM）作为对口服SIV BFT的抗性模型。通过对这两种动物模型的比较，我们将探讨HIV/SIV口腔BFT的机制，并探索预防HIV口腔传播的新策略。 除了使用暴露于母乳具有相反结果的两种动物模型外，我们还开发了：（1）一种新的挑战策略，包括剂量递增，我们在初步研究中证明了该策略可以准确模拟自然粘膜传播，同时有效感染动物;（2）新的挑战工具，由传播/创始感染性分子克隆（IMC）组成这使我们能够对SIV传播和SIVmac和SIVagm的分子标记IMC进行生理学建模，这为我们提供了IMC的优点以及监测传播瓶颈的可能性;（3）监测病毒传播和传播病毒多样性的新方法（实时单基因组扩增）。我们将逐步实现以下具体目标（SA）： SA 1.检验婴儿粘膜驱动SIV BFT疗效的假设。 SA1a。剖析牛奶与婴儿粘膜靶细胞水平在驾驶中的相对贡献 HIV-1 BFT。 SA1b.提供概念验证数据，即婴儿粘膜中靶细胞可用性的降低 降低SIV BFT利率。 SA 2.确定口服HIV/SIV BFT后病毒进入粘膜的部位，并评估与SIV BFT相关的早期粘膜变化。 SA2a。对潜在的进入部位进行“病毒学解剖”。 SA2b.确定通过母乳喂养经口暴露后SIV进入的确切部位以及与经口SIV传播相关的粘膜因素。 本案无关结合起来，这些研究在NHP物种中进行，这些物种对SIV BFT的易感性各不相同，采用创新的干预措施和新的分析工具，将描述负责口服SIV BFT的因素，并确定预防口服HIV传播的新策略。