Consequences of acute HIV infection on the EBV-specific immunity

EBV和KSHV驱动的口腔淋巴瘤的发展是HIV感染受试者中的严重临床问题。尽管其在一些地理区域，包括南部非洲， 在美国，很少有人知道疱疹病毒特异性免疫或缺乏免疫与疾病控制的关系。特别是，基本上没有关于急性艾滋病毒感染对先前存在的 EBV和KSHV特异性免疫及其对后期疾病表现的影响。这种知识的缺乏主要是由于后勤困难，以检查疱疹病毒特异性细胞免疫， 艾滋病毒感染前后的反应。如果能对艾滋病毒感染高危人群进行密切监测，并结合详细的免疫分析， 这是我们理解急性HIV感染期间的免疫事件如何使个体易于长期控制疱疹病毒感染的重要差距。本研究旨在建立这样的队列 并在HIV感染前后在单个表位水平上评估EBV和KSHV特异性免疫应答。使用敏感和多参数流式细胞术的方法，拟议的研究将有助于评估是否HIV感染导致一些疱疹病毒特异性T细胞反应的完全丧失，或者是否HIV感染导致这些反应性可能短暂的功能沉默。比较血液样本和扁桃体活检获得的细胞，研究将解决外周血中的变化是否是扁桃体中严重免疫畸变的结果，扁桃体是口腔传播病毒病毒复制的重要部位。扁桃体样本还将允许在本提案的项目2和项目3中进行病毒基因表达分析，有助于将检测到的免疫反应与该部位是否存在病毒抗原联系起来。总之，项目4中的分析将为围绕急性HIV感染的早期免疫事件提供独特的见解，并可能决定这些患者的疱疹病毒控制。 共同感染的受试者。在秘鲁利马的一个未经治疗的HIV队列中进行这些分析也将加深我们对该地理区域常见的针对疱疹病毒感染的细胞免疫的理解， 经常与口腔疾病表现有关。

The development of EBV and KSHV driven lymphomas in the oral cavity is a serious clinical issue in HIV infected subjects. Despite its relatively frequent occurrence in some geographic areas, including South America, little is known how the herpesvirus specific immunity or lack thereof, is associated with disease control. In particular essentially no data exist regarding the impact of acute HIV infection on the pre-existing EBV and KSHV specific immunity and its consequences for later disease manifestation. This lack of knowledge is largely due to logistical difficulties to examine the herpesvirus-specific cellular immune response in individuals immediately before and after HIV infection. The availability of a closely monitored cohort of individuals at high risk for HIV infection, combined with detailed immune analyses would overcome this important gap in our understanding how immune events during acute HIV infection predispose individuals for long-term control of herpesviral infections. The present study aims to establish such as cohort and to assess EBV and KSHV specific immune responses on a single epitope level before and after HIV infection. Using sensitive and multi-parameter flow-cytometryapproaches the proposed studies will help to assess whether HIV infection leads to a complete loss of some herpesvirus specific T cell responses or whether HIV infection leads to a possibly transient functional silencing of these reactivities. Comparing blood samples to cells obtained form tonsilar biopsies, the studies will address whether the changes in the peripheral blood are a consequence of profound immune aberrations in the tonsil, an important site of viral replication for orally transmitted viruses. The tonsil samples will also allow to perform viral gene expression analyses in projects 2 and 3 of this proposal, helping to link detected immune responses to the presence or absence of viral antigens in this site. Together, the analyses in project 4 will provide unique insight into the early immune events that surround acute HIV infection and that may determine herpesvirus control in these co-infected subjects. Performing these analyses in a untreated HIV cohort in Lima, Peru will also deepen our understanding of cellular immunity against herpesvirus infections common to this geographic area and frequently associated with disease manifestation in the oral cavity.