Pathogenesis of oral rhesus lymphocryptovirus infection

爱泼斯坦-巴尔病毒是一种经口传播的疱疹病毒，在成年期持续感染几乎所有人。 原发性EB病毒感染与剧烈的裂解性复制有关，如口腔分泌物中的病毒脱落所证明 和对许多裂解蛋白的强血清学应答，以及大量潜伏感染的B细胞。但据 裂解性复制是否是急性感染期间病毒扩增的主要机制以及 [ytic复制是侵入外周血所必需的，其中B细胞感染对于建立生命是关键的， 长期持续感染。这些问题在人类中很难解决，因为急性原发性感染通常不 除非发生传染性单核细胞增多症，通常发生在口服病毒接种后数周， 初始感染。 我们已经开发了一种EB病毒感染的模型，使用一种与自然感染恒河猴密切相关的疱疹病毒 猕猴，并且与EBV属于相同的淋巴隐病毒（LCV）属。rhLCV基因组序列揭示了 rhLCV感染与EBV感染具有几乎相同的生物学特性。RhLCV初治 恒河猴可以通过实验感染，从而可以在口服接种后立即进入这一时期。 在上一个资助期间，我们已经确定了口服接种后急性感染的参数， 免疫活性宿主和通过与嵌合人/猿共感染而免疫抑制的宿主 免疫缺陷病毒（SHIV）。值得注意的是，我们发现rhLCV感染可能与以下疾病的发生有关： 艾滋病患者中类似口腔毛状白斑的B细胞淋巴瘤和增生性上皮病变。另外我们 描述了CD 8 + T细胞对裂解和潜伏rhLCV蛋白的应答。该模型系统的开发目前 使我们能够详细地说明裂解病毒复制在免疫活性的急性感染过程中的作用， 免疫抑制宿主，用于以下特定目的： 具体目标#1 -口服接种后病毒复制在原发性rhLCV感染中的作用 免疫活性的恒河猴 具体目标#2 -口服接种后病毒复制在原发性rhLCV感染中的作用 SHIV免疫抑制恒河猴？ 具体目标#3 -在急性rhLCV感染中，对裂解蛋白具有特异性的CD 8 + CTL多早出现？ 这些研究将阐明裂解性病毒复制的作用和急性感染期间的免疫应答， 否则很难或不可能在人类身上进行研究。更好地理解溶解性蛋白质与 EBV感染和对裂解性EBV蛋白的免疫应答将有助于开发新的治疗药物， 用于控制EBV感染和与裂解性EBV复制相关的疾病的方法，例如口腔毛状疱疹， 白斑病

Epstein-Barr virus is an orally transmitted herpesvirus that persistently infects nearly all humans by adulthood. Primary EBV infection is associated with vigorous lytic replication, as evidenced by viral shedding in oral secretions and robust serologic responses to many lytic proteins, and high numbers of latently infected B cells. However, it is unknown whether lytic replication is the primary mechanism for viral amplificationduring acute infection and whether [ytic replication is required for invasion of the peripheral blood where B cell infection is critical for establishing life, long persistent infection. These questions are difficult to address in humans since acute, primary infection is not usually recognized unless infectious mononucleosis develops, and this typically occurs weeks after oral virus inoculation and initial infection. We have developed a model for EBV infection using a closely related herpesvirus that naturally infects rhesus macaques and is in the same lymphocryptovirus (LCV) genus as EBV. The rhLCV genome sequence reveals an identical gene repertoire to EBV, and rhLCV infection has virtually identical biology to EBV infection. RhLCV naive rhesus macaques can be experimentally infected allowing access to the period immediately following oral inoculation. In the previous funding period, we have defined the parameters of acute infection after oral inoculation in both immunocompetent hosts and hosts immunosuppressed by co-infectionwith a chimeric human/simian immunodeficiency virus (SHIV). Of note, we showed that rhLCV infection can be associated with the development of B cell lymphomas and proliferative epithelial lesions similar to oral hairy leukoplakia in AIDS patients. In addition, we described the CD8+ T cell responses to lytic and latent rhLCV proteins. The development of this model system now allows us to address in detail the role of lytic viral replication during acute infection of immunocompetent and immunosuppressed hosts in the following specific aims: Specific Aim #1 - What is the role of viral replication in primary rhLCV infection after oral inoculation of immunocompetent rhesus macaques? Specific Aim #2 - What is the role of viral replication in primary rhLCV infection after oral inoculation of SHIV immunosuppressed rhesus macaques? Specific aim #3 - How early do CD8+ CTL specific for lytic proteins develop in acute rhLCV infection? These studies will elucidate the role of lytic viral replication and the immune response during acute infection that would otherwise be difficult, or impossible, to study in humans. A better understanding of the interplay between lytic EBV infection and the immune response to lytic EBV proteins will contribute to development of novel therapeutic approaches for control of EBV infection and diseases associated with lytic EBV replication, such as oral hairy leukoplakia.