FACTORS INFLUENCING ORAL TRANSMISSION OF SIV

影响 SIV 口腔传播的因素

• 批准号: 8172677
• 负责人: Donald L Sodora
• 金额: $ 9.91万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8172677
• 关键词: Acquired Immunodeficiency Syndrome; African; Animal Model; Biological Models; Blood; Breast Feeding; Cells; Cellular Tropism; Child; Chronic Disease; Computer Retrieval of Information on Scientific Projects Database; Disease Progression; Dose; Event; Funding; Gingivitis; Goals; Grant; HIV; HIV Infections; HIV-1; Human; Human Milk; Immune; Immune response; Immunity; Infection; Infection prevention; Inflammation; Institution; Knowledge; Laboratories; Macaca; Macaca mulatta; Membrane; Modeling; Mothers; Mucous Membrane; Nature; Oral; Oral Sex; Oral cavity; Oral mucous membrane structure; Pathogenesis; Pattern; Primates; Probability; Proteins; Regimen; Research; Research Personnel; Resources; Route; SIV; Sampling; Seminal fluid; Source; Surface; Time; Tissues; United States National Institutes of Health; Vaccines; Vertical Disease Transmission; Viral; Virus; Work; design; experience; immune activation; lymph nodes; mucosal site; success; transmission process

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Currently, more than 40 million people worldwide are persistently infected with HIV-1. Similar to HIV infection in humans, SIV infection in non-African primate species results in chronic disease that culminates in AIDS. The well-defined SlV infection of rhesus macaques is an excellent animal model system to assess HIV transmission and pathogenesis for several reasons. SIV infection In macaques closely resembles many aspects of HIV infection in humans including events associated with transmission, cellular tropism of the virus, viral replication patterns. disease progression, and the nature of the host immune response. Furthermore, the SIV/macaque model is important because knowledge of the time, route, and number of viral exposures Is known, the viral stock used to infect the macaques is well-characterized, and there is the ability to frequently sample important tissues (blood, lymph nodes, mucosal sites, etc) throughout infection. For HIV and SIV, the major mode of transmission for new infections is mucosal transmission, i.e. the virus has to pass through a mucosal membrane to infect the new host However, the probability to become infected from a mucosa] encounter is actually quite low. A variety of factors contribute to this low probability, including inhibitory proteins at mucosal surfaces, the difficulty to pass an intact mucosal membrane and the probability for the virus to find a suitable target cell to Infect Initially as soon as it passes the membrane. Using the macaque model, our laboratory has focused its work on oral transmission of HlV/SIV, a route that is important for mother-to-child (vertical) transmission through breast feeding and for transmission during oral sex when virus is present in semen. However, it still remains unclear what the most important events are which permit the actual transmission itself. Here we expand upon our previous findings by assessing the impact of immune activation on the transmission of SIV administered into the oral cavity of macaques. We hypothesize that higher levels of immune activation will increase the potential for SIV to elicit a productive infection. These studies will utilize a low dose regimen of viral Inoculations to mimic the viral levels that are present in breast milk and semen. We will assess transmission of SIV while the mucosa is experiencing a state of immune activation, gingivitis. Gingivitis is a common inflammation of the oral mucosa in humans and therefore may be impacting oral transmission in humans exposed to HIV containing semen (through receptive oral intercourse). These studies assessing the impact of the immune response on oral transmission are likely be applicable to other sites of mucosal transmission, and will be important for determining the immune mechanisms that impact the success of SIV/HIV mucosal transmission. Our long term goal is to utilize these findings to aid in the design of SIV/HlV vaccines that are able to elicit sterilizing immunity by preventing the infection of the first target cell when mucosal sites are exposed to HIV/SIV.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 目前，全世界有超过 4000 万人持续感染 HIV-1。与人类的 HIV 感染类似，非非洲灵长类动物的 SIV 感染会导致慢性疾病，最终导致艾滋病。出于多种原因，明确定义的恒河猴 SlV 感染是评估 HIV 传播和发病机制的绝佳动物模型系统。猕猴中的 SIV 感染与人类 HIV 感染的许多方面非常相似，包括与传播、病毒的细胞向性、病毒复制模式相关的事件。疾病进展以及宿主免疫反应的性质。此外，SIV/猕猴模型很重要，因为已知病毒暴露的时间、途径和数量，用于感染猕猴的病毒储备具有良好的特征，并且能够经常对重要组织（血液）进行采样。 、淋巴结、粘膜部位等）整个感染过程中。对于HIV和SIV来说，新感染者的主要传播方式是粘膜传播，即病毒必须穿过粘膜才能感染新宿主，但从粘膜接触感染的概率其实很低。造成这种低概率的因素有多种，包括粘膜表面的抑制蛋白、穿过完整粘膜的难度以及病毒在穿过膜后立即找到合适的靶细胞进行感染的可能性。我们的实验室利用猕猴模型，将工作重点放在 HIV/SIV 的口腔传播上，这种途径对于通过母乳喂养进行的母婴（垂直）传播以及精液中存在病毒时的口交传播非常重要。然而，目前仍不清楚哪些最重要的事件允许实际传输本身。在这里，我们通过评估免疫激活对给予猕猴口腔的 SIV 传播的影响来扩展我们之前的发现。我们假设较高水平的免疫激活将增加 SIV 引发生产性感染的可能性。这些研究将利用低剂量的病毒接种方案来模拟母乳和精液中存在的病毒水平。我们将评估当粘膜处于免疫激活状态（牙龈炎）时 SIV 的传播情况。牙龈炎是人类口腔粘膜的常见炎症，因此可能会影响暴露于含有艾滋病毒的精液（通过接受性口交）的人类的口腔传播。这些评估免疫反应对口腔传播影响的研究可能适用于粘膜传播的其他部位，并且对于确定影响 SIV/HIV 粘膜传播成功的免疫机制非常重要。我们的长期目标是利用这些发现来帮助设计 SIV/HIV 疫苗，当粘膜部位暴露于 HIV/SIV 时，这些疫苗能够通过防止第一个靶细胞的感染来引发灭菌免疫。