RHESUS HHV8 HOMOLOGUE IN AIDS-RELATED MALIGNANCIES

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 我的实验室正在利用猴免疫缺陷病毒(SIV)/恒河猴横纹病毒(RRV)/恒河猴(RM)动物模型来阐明RRV如何能够重现人类疱疹病毒8型(HHV8)能够在艾滋病患者中诱导的许多淋巴增殖性疾病(LPD)。这些疾病包括多中心性Castleman病(MCD)和非霍奇金淋巴瘤(NHL)。在过去的一年里，我们在传染性和致病性恒河猴杆状病毒细菌人工染色体(BAC)方面取得了成功，取得了重大进展。这种RRV-BAC在转基因的恒河猴成纤维细胞中产生传染性病毒(BAC衍生病毒)，能够诱导SIV感染的RM中的B细胞增殖。更重要的是，实验中感染了BAC衍生病毒的SIV感染的RM会出现持续性淋巴病变，很像野生型RRV感染。这些都是重要和必要的研究，将导致识别致病的病毒决定因素。我们最初的重点是那些在HHV8和RRV之间保守的病毒ORF和大分子。这些包括病毒干扰素调节因子(VIRFs)、病毒CD200(VCD200)同系物和病毒编码的miRNAs。为此，我们创造了三个缺乏表达这些特定病毒ORF的能力的重组体。缺少8个vIRFs的重组体能够在细胞培养中生长，但不能在实验感染的动物身上复制。第二个重组体包含vCD200的无义突变。这种重组体在细胞培养中生长良好，并能够在动物中建立持续感染。有趣的是，这些动物的病毒载量高于感染野生型病毒并患有RRV相关疾病的动物。

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. My laboratory is utilizing the simian immunodeficiency virus (SIV)/rhesus rhadinovirus (RRV)/rhesus macaque (RM) animal model to elucidate how RRV is able to recapitulate many of the lymphoproliferative disorders (LPD) that human herpesvirus 8 (HHV8) is capable of inducing in AIDS patients. These include multicentric Castleman's disease (MCD) and non-Hodgkin's lymphoma (NHL). During the past year we have made significant progress, building upon our success with the infectious and pathogenic rhesus rhadinovirus bacterial artificial chromosome (BAC). This RRV-BAC produces infectious virus (BAC-derived virus) in transfected rhesus fibroblasts that is capable of inducing B cell hyperplasia in SIV-infected RM. More importantly, SIV-infected RM experimentally infected with the BAC-derived virus develops persistent lymphadenopathy, much like wild-type RRV infection. These are important and essential studies which will lead to the identification of viral determinants of pathogenesis. Our initial focus has been on those viral ORFs and macromolecules that are conserved between HHV8 and RRV. These include the viral interferon regulatory factors (vIRFs), viral CD200 (vCD200) homologue and the viral encoded miRNAs. To this end, we have created three recombinants that lack the ability to express these specific viral ORFs. The recombinant lacking the eight vIRFs is capable of growth in cell culture, but is unable to replicate in experimentally infected animals. The second recombinant contains a nonsense mutation in the vCD200. This recombinant grows well in cell culture and is capable of establishing a persistent infection in animals. Interestingly, these animals have higher viral loads than animals infected with wild-type virus and present with RRV-associated disease.