PDF(Pubmed)
Abstract：
Marek\'s disease virus (MDV) vaccines were the first vaccines that protected against cancer. The avirulent turkey herpesvirus (HVT) was widely employed and protected billions of chickens from a deadly MDV infection. It is also among the most common vaccine vectors providing protection against a plethora of pathogens. HVT establishes latency in T-cells, allowing the vaccine virus to persist in the host for life. Intriguingly, the HVT genome contains telomeric repeat arrays (TMRs) at both ends; however, their role in the HVT life cycle remains elusive. We have previously shown that similar TMRs in the MDV genome facilitate its integration into host telomeres, which ensures efficient maintenance of the virus genome during latency and tumorigenesis. In this study, we investigated the role of the TMRs in HVT genome integration, latency, and reactivation in vitro and in vivo. Additionally, we examined HVT infection of feather follicles. We generated an HVT mutant lacking both TMRs (vΔTMR) that efficiently replicated in cell culture. We could demonstrate that wild type HVT integrates at the ends of chromosomes containing the telomeres in T-cells, while integration was severely impaired in the absence of the TMRs. To assess the role of TMRs in vivo, we infected one-day-old chickens with HVT or vΔTMR. vΔTMR loads were significantly reduced in the blood and hardly any virus was transported to the feather follicle epithelium where the virus is commonly shed. Strikingly, latency in the spleen and reactivation of the virus were severely impaired in the absence of the TMRs, indicating that the TMRs are crucial for the establishment of latency and reactivation of HVT. Our findings revealed that the TMRs facilitate integration of the HVT genome into host chromosomes, which ensures efficient persistence in the host, reactivation, and transport of the virus to the skin.
摘要：
马立克氏病病毒（MDV）疫苗是第一个预防癌症的疫苗。无毒火鸡疱疹病毒（HVT）被广泛使用，并保护了数十亿只鸡免受致命的MDV感染。它也是提供针对过多病原体的保护的最常见的疫苗载体之一。HVT在T细胞中建立潜伏期，允许疫苗病毒在宿主体内存活。有趣的是，HVT基因组在两端含有端粒重复序列(TMR);然而,它们在HVT生命周期中的作用仍然难以捉摸。我们以前已经表明，MDV基因组中相似的TMR有助于其整合到宿主端粒中，这确保了病毒基因组在潜伏期和肿瘤发生过程中的有效维持。在这项研究中,我们研究了TMR在HVT基因组整合中的作用，延迟，并在体外和体内重新激活。此外,我们检查了羽毛卵泡的HVT感染。我们产生了缺乏两种TMR(vΔTMR)的HVT突变体,其在细胞培养物中有效复制。我们可以证明野生型HVT整合在包含T细胞端粒的染色体末端，而在没有TMR的情况下整合严重受损。为了评估TMR在体内的作用，我们用HVT或vΔTMR感染了一天大的鸡。血液中的vΔTMR负荷显着降低，几乎没有任何病毒被转运到羽毛滤泡上皮，在那里病毒通常会脱落。引人注目的是，在缺乏TMR的情况下，脾脏的潜伏期和病毒的再激活受到严重损害，表明TMR对于建立延迟和重新激活HVT至关重要。我们的发现揭示了TMR促进HVT基因组整合到宿主染色体中,这确保了主机中的有效持久性，重新激活,并将病毒运送到皮肤。
