Imperial College London, St Mary's Hospital, Department of Infectious Disease, Section of Virology, Norfolk Place, London, W2 1PG, UK.
Chromatin Structure and Mobile DNA Laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.
Nat Commun. 2020 Oct 7;11(1):5043. doi: 10.1038/s41467-020-18874-y.
Human T-cell lymphotropic virus type 1 (HTLV-1) is a deltaretrovirus and the most oncogenic pathogen. Many of the ~20 million HTLV-1 infected people will develop severe leukaemia or an ALS-like motor disease, unless a therapy becomes available. A key step in the establishment of infection is the integration of viral genetic material into the host genome, catalysed by the retroviral integrase (IN) enzyme. Here, we use X-ray crystallography and single-particle cryo-electron microscopy to determine the structure of the functional deltaretroviral IN assembled on viral DNA ends and bound to the B56γ subunit of its human host factor, protein phosphatase 2 A. The structure reveals a tetrameric IN assembly bound to two molecules of the phosphatase via a conserved short linear motif. Insight into the deltaretroviral intasome and its interaction with the host will be crucial for understanding the pattern of integration events in infected individuals and therefore bears important clinical implications.
人类 T 细胞嗜淋巴细胞病毒 1 型（HTLV-1）是一种δ逆转录病毒，也是最具致癌性的病原体。在约 2000 万感染 HTLV-1 的人中，许多人会患上严重的白血病或类似 ALS 的运动疾病，除非有治疗方法。感染建立的关键步骤是病毒遗传物质被逆转录病毒整合酶（IN）酶整合到宿主基因组中。在这里，我们使用 X 射线晶体学和单颗粒冷冻电子显微镜技术，确定了功能性δ逆转录病毒 IN 在病毒 DNA 末端组装并与人类宿主因子蛋白磷酸酶 2A 的 B56γ 亚基结合的结构。该结构揭示了一个四聚体 IN 组装体通过保守的短线性基序与两种磷酸酶分子结合。对δ逆转录病毒整合酶体及其与宿主的相互作用的深入了解对于理解感染个体中整合事件的模式至关重要，因此具有重要的临床意义。
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