CELLULAR HOMOLOGS IN A NEW SIMIAN GAMMAHERPESVIRUS

在与华盛顿地区灵长类动物研究中心（WRPRC）的合作努力中，我们在两种猕猴物种M. nemestrina （Mn）和M. mulatta （Mm）的RF病变中发现了三种与卡波西氏肉瘤相关疱疹病毒（KSHV）相关的伽玛疱疹病毒。RF是一种快速致命的侵袭性增殖肿瘤，与KS有形态学上的相似之处。最近的研究表明KSHV在KS的发病机制中起病原学作用。两种新的猕猴病毒RFHVMn和RFHVMm彼此密切相关，并与KSHV密切相关。第三种是nemestrina rhadinvirus (NRV)，它与另一种来自M. mulatta的伽马疱疹病毒（rhesus rhadinvirus， RRV）密切相关。我们将这些病毒归为一个新的伽玛3疱疹病毒属，其中伽玛3a亚群包括KSHV、RFHVMn和RFHVMm，伽玛3b亚群包括NRV和RRV。随着NRV的发现，我们现在已经确定，所有研究RF肿瘤的猕猴要么感染了gamma3A病毒，要么感染了gamma3B病毒，或者同时感染了两组病毒。这些结果支持了我们的假设，即猕猴的kshv样疱疹病毒在RF的发病机制中起病原学作用，SRV-2相关RF是研究AIDS- KS的相关动物模型。我们目前正在表征RFHVMn/Mm和NRV的基因组，以便将它们与KSHV和RRV进行比较。我们对生长调节基因的病毒同源物特别感兴趣，这对病毒致病性很重要。为了研究gamma3A和gamma3B猕猴病毒之间的生物学和病理学差异，我们研究了细胞趋向性、基因激活以及与SRV-2的相互作用。我们的长期目标是确定这些类型的疱疹病毒与逆转录病毒和内源性细胞因子在诱导和进展ks样恶性肿瘤中的作用和相互作用。对于这项申请，我们提出以下具体目标：1)确定猕猴γ - 3a疱疹病毒RFHVMn的基因组组织；2)鉴定和表征参与生长调控和细胞转化的细胞基因的RFHVMn同源基因；3)确定猕猴γ - 3a和γ - 3b kshv样疱疹病毒和SRV-2在感染猕猴RF肿瘤和非肿瘤组织中的细胞趋向性和复制状态。4)建立猕猴伽玛3a和伽玛3b kshv样疱疹病毒感染周期基线参数。

In a collaborative effort with the Washington Regional Primate Research Center (WRPRC) we have discovered three gammaherpesviruses related to Kaposi's Sarcoma-associated herpesvirus (KSHV) in RF lesions of two macaque species, M. nemestrina (Mn) and M. mulatta (Mm). RF is an aggressively proliferating tumor which is rapidly fatal, and has morphological similarities to KS. Recent studies suggest that KSHV plays an etiological role in the pathogenesis of KS. Two of the new macaque viruses, RFHVMn and RFHVMm are closely related to each other and to KSHV. The third, nemestrina rhadinovirus (NRV), is closely related to another gammaherpesvirus from M. mulatta, called rhesus rhadinovirus (RRV). We group these viruses in a new gamma3 genus of herpesviruses with a gamma3A subgroup consisting of KSHV, RFHVMn and RFHVMm and a gamma3B subgroup consisting of NRV and RRV. With the discovery of NRV, we have now determined that all the macaques studied with RF tumors were infected with either a gamma3A or gamma3B virus, or were co- infected with viruses from both groups. These results support our hypothesis that KSHV-like herpesviruses of macaques play an etiological role in the pathogenesis of RF and that SRV-2 associated RF is a relevant animal model for the study of AIDS- KS. We are currently characterizing the genomes of RFHVMn/Mm and NRV in order to compare them to KSHV and RRV. We are especially interested in viral homologs of growth regulatory genes which appear important for viral pathogenicity. To study the biological and pathological differences between the gamma3A and gamma3B macaque viruses, we are examining cellular tropism, gene activation and interactions with SRV-2. Our long term goal is to determine the contributions and interactions of these types of herpesviruses with retroviruses and endogenous cellular factors in the induction and progression of KS-like malignancies. For this application, we propose the following specific aims: 1) Determine the genomic organization of the macaque gamma3A herpesvirus, RFHVMn, 2) Identify and characterize RFHVMn homologs of cellular genes involved in growth regulation and cellular transformation, 3) Determine the cellular tropism and replicative state of macaque gamma3A and gamma3B KSHV-like herpesviruses and SRV-2 in RF tumors and non-tumor tissue from infected macaques, 4) Establish the baseline parameters of the infectious cycle of the macaque gamma3A and gamma3B KSHV-like herpesviruses.