Molecular mechanism of human herpesvirus 6 latent infector

人巨细胞病毒(CMV)是免疫功能低下的个体和新生儿的重要病原体。人类疱疹病毒6型(HHV-6)是一种引起皮疹的病原体。这两种病毒属于b-疱疹病毒亚科。潜伏期是所有疱疹病毒的标志，但对b-疱疹病毒仍知之甚少。我们使用巨细胞病毒的粒细胞-巨噬细胞前体细胞(GM-Ps)和HHV-6的单核/巨噬细胞，研究了实验性潜伏感染中病毒基因组的维持和表达。感染巨细胞病毒后，人类GM-P携带病毒基因组，但无法支持生产性复制。HHV-6在人类单核/巨噬细胞中维持其基因组。为了更好地了解b-疱疹病毒的潜伏期，我们调查了病毒基因在我们的潜伏期系统中的表达程度，发现了两类新的CMV潜伏期相关转录本(CLT)和HHV-6潜伏期转录本(HHV-6LT)。我们的特征是这些转录本和CLT可以在健康CMV血清阳性成人的骨髓抽提物和健康个体的HHV-6LT中检测到。在CMV和HHV-6的情况下，病毒转录本产生于主要调控基因位点周围的区域；然而，它们的结构与生产阶段的转录本显著不同。在巨细胞病毒的情况下，这些转录本有可能编码新的94和152aa蛋白。在HHV-6新病毒中，99aa、279aa、91aa和160aa蛋白被编码。因此，CMV和HHV-6的潜伏感染伴随着潜伏相关转录本的存在和免疫原蛋白的表达。总之，这些结果表明，骨髓来源的髓系祖细胞是CMV潜伏期的重要自然部位，而外周血来源的单核/巨噬细胞对维持HHV-6潜伏期是重要的。

Human cytomegalovirus (CMV) is a significant pathogen in immunocompromised individuals and neonates. Human herpesvirus 6 (HHV-6) is a causative agent of exanthem subitum. These two virusues belong to b-herpesvirus subfamily. Latency, a hallmark of all herpesvirus, remains poorly understood for b-herpesvirus. We investigate maintenance and expression of the viral genome in an experimental latent infection using granulocyte-macrophage progenitors (GM-Ps) for CMV and monocytes/macrophages for HHV-6. Following infection with cytomegalovirus, human GM-Ps carry the viral genome but fail to support productive replication. HHV-6 maintein its genome in human monocytes/macrophages.To better understand b-herpesvirus latency, we investigate the extent of viral gene expression in our latency system and found two novel classes of CMV latency associated transcripts (CLTs) and HHV-6 latency transcript (HHV-6LT). We characterize these transcripts and CLTs can be detected in BM aspirates from healthy CMV seropositive adults and HHV-6LT from healthy individuals. Both in the case of CMV and HHV-6, viral transcripts arise from a region encompassing the major regulatory gene locus ; however, their structure differs significantly from productive phase transcripts. In the case of CMV, these transcripts have the potential to encode novel 94 and 152aa proteins. In HHV-6 novel 99aa, 279aa, 91aa and 160aa proteins are encorded. Thus, latent infection by CMV and HHV-6 is accompanied by the presence of latency-associated transcripts and expression of immunogenic proteins. Overall, these results suggest that bone marrow-derived myeloid progenitors are an important natural site of CMV latency and peripheral blood derived monocytes/macrophages is important to maintein HHV-6 latency.