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，成年后几乎所有人都会持续感染。 原发EBV感染与活跃的裂解复制有关，口腔分泌物中的病毒脱落证明了这一点 对许多裂解蛋白的强劲血清学反应，以及大量潜伏感染的B细胞。然而，它是 未知在急性感染期间，裂解复制是否是病毒扩增的主要机制，以及 [溶血复制是侵入外周血液所必需的，在外周血液中，B细胞感染对建立生命至关重要， 长期持续感染。这些问题很难在人类身上解决，因为急性、原发感染通常不是 除非出现传染性单核细胞增多症，这通常发生在口服病毒接种和 最初的感染。 我们利用一种密切相关的疱疹病毒自然感染恒河猴，开发了一种EB病毒感染模型。 与EB病毒同属淋巴病毒(LCV)。重组人LCV基因组序列揭示了 与EBV具有相同的基因谱系，而重组人LCV感染与EBV感染具有几乎相同的生物学特性。RhLCV幼稚 恒河猴可以被实验感染，从而进入口服接种后的紧随时期。 在之前的资助期间，我们已经确定了两个国家口服疫苗后急性感染的参数 免疫活性宿主和与人/猴嵌合感染联合感染的宿主免疫抑制 免疫缺陷病毒(SIV)。值得注意的是，我们发现rh LCV感染可能与慢性粒细胞白血病的发生有关。 艾滋病患者B细胞淋巴瘤和类似口腔毛状白斑的增生性上皮病变。此外，我们 描述了CD8+T细胞对裂解和潜伏的重组人LCV蛋白的反应。该模型系统目前的发展状况 使我们能够详细地研究裂解病毒复制在免疫活性和急性感染期间的作用 免疫抑制宿主具有以下特定目的： 特定目标#1-口服接种后病毒复制在原发重组人LCV感染中的作用 免疫能力强的恒河猴？ 特定目标2-口服接种后病毒复制在原发重组人LCV感染中的作用是什么 希沃克病毒免疫抑制恒河猴？ 特定目标#3--在急性重组人LCV感染中，CD8+CTL对溶解蛋白的特异性形成有多早？ 这些研究将阐明溶血性病毒复制和免疫反应在急性感染中的作用 否则，在人类身上研究将是困难的，或者是不可能的。更好地理解Lytic之间的相互作用 EBV感染和对EBV裂解蛋白的免疫应答将有助于开发新的治疗方法 控制EBV感染和与EBV裂解复制相关的疾病的方法，如口腔毛发 黏膜白斑。

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.