Bertzbach Luca D, You Yu, Vychodil Tereza, Kheimar Ahmed, Kossak Lisa, Sabsabi Mohammad A, Conradie Andelé M, Kaufer Benedikt B
Institute of Virology, Freie Universität Berlin, Berlin, Germany.
Research Unit Emerging Diseases, Leibniz Institute of Virology (LIV), Hamburg, Germany.
mSphere. 2025 May 27;10(5):e0014225. doi: 10.1128/msphere.00142-25. Epub 2025 May 8.
Marek's disease virus (MDV) is a highly oncogenic alphaherpesvirus that causes fatal T cell lymphomas in chickens. Oncogenic MDV strains can integrate their genome into the host telomeres of latently infected and tumor cells. This integration process is facilitated by telomeric repeat arrays (TMR) present at the ends of the MDV genome, which consist of the hexanucleotide (TTAGGG) that is identical to host telomere sequences. In addition, integration of the virus genome is crucial for the development of lymphomas. Live-attenuated vaccines play a vital role in protecting chickens against this deadly disease, yet our understanding of their biology remains limited. Intriguingly, the commercial gold standard MDV vaccine, the live-attenuated MDV strain CVI988, also possesses TMR at the ends of its genome. In this study, we investigated the role of the multiple TMR arrays (mTMR) in vaccine virus integration, latency, reactivation, and protection against very virulent MDV. Our data revealed that the mTMR present in CVI988 are important for virus genome integration and maintenance in latently infected cells . In addition, virus latency, reactivation, and vaccine efficacy were reduced in an mTMR deleted mutant compared to the wild-type vaccine. These results provide valuable insights into the biology of this important vaccine virus and shed light on the roles of the mTMR in vaccine integration, latency, and protection against very virulent MDV.IMPORTANCEMarek's disease virus (MDV) is an oncogenic herpesvirus and causes lethal lymphomas in chickens. The gold standard vaccine is the live-attenuated MDV strain CVI988 (a.k.a. Rispens). CVI988 is extensively used in chickens worldwide due to its high efficacy in preventing disease and lymphomas. The CVI988 vaccine harbors telomere arrays (TMR) at the ends of its genome. TMR facilitate genome integration of oncogenic MDV strains into the host telomeres. This study provides critical insights into the biology of the widely used MDV vaccine strain CVI988, demonstrating the crucial role of mTMR in viral genome integration, latency, and protection against very virulent MDV. Furthermore, our findings enhance the understanding of MDV vaccine biology and may guide future strategies to improve Marek's disease control.
马立克氏病病毒（MDV）是一种高度致癌的α疱疹病毒，可在鸡体内引发致命的T细胞淋巴瘤。致癌性MDV毒株可将其基因组整合到潜伏感染细胞和肿瘤细胞的宿主端粒中。MDV基因组末端存在的端粒重复序列（TMR）促进了这一整合过程，该序列由与宿主端粒序列相同的六核苷酸（TTAGGG）组成。此外，病毒基因组的整合对于淋巴瘤的发展至关重要。减毒活疫苗在保护鸡免受这种致命疾病侵害方面发挥着至关重要的作用，但我们对其生物学特性的了解仍然有限。有趣的是，商业金标准MDV疫苗，即减毒活MDV毒株CVI988，在其基因组末端也具有TMR。在本研究中，我们调查了多个TMR阵列（mTMR）在疫苗病毒整合、潜伏、再激活以及抵御超强毒力MDV方面的作用。我们的数据表明，CVI988中存在的mTMR对于病毒基因组在潜伏感染细胞中的整合和维持非常重要。此外，与野生型疫苗相比，mTMR缺失突变体的病毒潜伏、再激活和疫苗效力均有所降低。这些结果为这种重要疫苗病毒的生物学特性提供了有价值的见解，并揭示了mTMR在疫苗整合、潜伏以及抵御超强毒力MDV方面的作用。
重要性
马立克氏病病毒（MDV）是一种致癌性疱疹病毒，可在鸡体内引发致命的淋巴瘤。金标准疫苗是减毒活MDV毒株CVI988（又名Rispens）。由于CVI988在预防疾病和淋巴瘤方面具有高效性，因此在全球范围内广泛用于养鸡业。CVI988疫苗在其基因组末端含有端粒阵列（TMR）。TMR促进致癌性MDV毒株的基因组整合到宿主端粒中。本研究为广泛使用的MDV疫苗毒株CVI988的生物学特性提供了关键见解，证明了mTMR在病毒基因组整合、潜伏以及抵御超强毒力MDV方面的关键作用。此外，我们的研究结果加深了对MDV疫苗生物学特性的理解，并可能指导未来改善马立克氏病防控的策略。
