FACTORS INFLUENCING ORAL TRANSMISSION OF SIV

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 目前，全球有4000多万人持续感染艾滋病毒-1。与人类感染艾滋病毒类似，非非洲灵长类动物感染SIV会导致慢性疾病，最终导致艾滋病。由于多种原因，恒河猴SLV感染是评估HIV传播和发病机制的一个很好的动物模型系统。猕猴的SIV感染与人类HIV感染的许多方面非常相似，包括与传播相关的事件、病毒的细胞嗜性、病毒复制模式。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、路线和数量，感染猕猴所用的病毒库具有良好的特性，并且能够在感染过程中经常对重要组织(血液、淋巴结、粘膜部位等)进行采样。对于艾滋病毒和SIV，新感染的主要传播方式是粘膜传播，即病毒必须通过粘膜才能感染新宿主，然而，从粘膜接触感染的可能性实际上相当低。多种因素导致这种低概率，包括粘膜表面的抑制蛋白，难以通过完整的粘膜，以及病毒一通过膜就找到合适的目标细胞进行初始感染的可能性。利用猕猴模型，我们的实验室将工作重点放在HLV/SIV的口服传播上，这一途径对于通过母乳喂养的母婴(垂直)传播以及当病毒存在于精液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本身允许实际传播。在这里，我们通过评估免疫激活对SIV进入猕猴口腔内传播的影响来扩展我们之前的发现。我们假设，更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SIV在黏膜处于免疫激活状态时的传播情况，即牙周炎。牙龈炎是人类常见的口腔黏膜炎症，因此可能会影响接触含艾滋病毒精液的人的口腔传播(通过接受性口腔性交)。这些评估免疫反应对口腔传播影响的研究可能适用于其他黏膜传播部位，对于确定影响SIV/HIV黏膜传播成功的免疫机制将是重要的。我们的长期目标是利用这些发现来帮助设计SIV/HLV疫苗，这种疫苗能够在粘膜部位暴露于HIV/SIV时防止第一个目标细胞的感染，从而诱导灭菌免疫。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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.