Division of Gynecological Oncology, Department of Obstetrics and Gynecology, Ulm University, Ulm, Germany.
Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany.
Nat Microbiol. 2020 Oct;5(10):1247-1261. doi: 10.1038/s41564-020-0753-6. Epub 2020 Jul 20.
To avoid innate sensing and immune control, human immunodeficiency virus type 1 (HIV-1) has to prevent the accumulation of viral complementary DNA species. Here, we show that the late HIV-1 accessory protein Vpu hijacks DNA repair mechanisms to promote degradation of nuclear viral cDNA in cells that are already productively infected. Vpu achieves this by interacting with RanBP2-RanGAP1*SUMO1-Ubc9 SUMO E3-ligase complexes at the nuclear pore to reprogramme promyelocytic leukaemia protein nuclear bodies and reduce SUMOylation of Bloom syndrome protein, unleashing end degradation of viral cDNA. Concomitantly, Vpu inhibits RAD52-mediated homologous repair of viral cDNA, preventing the generation of dead-end circular forms of single copies of the long terminal repeat and permitting sustained nucleolytic attack. Our results identify Vpu as a key modulator of the DNA repair machinery. We show that Bloom syndrome protein eliminates nuclear HIV-1 cDNA and thereby suppresses immune sensing and proviral hyper-integration. Therapeutic targeting of DNA repair may facilitate the induction of antiviral immunity and suppress proviral integration replenishing latent HIV reservoirs.
为了避免先天感应和免疫控制，人类免疫缺陷病毒 1 型（HIV-1）必须防止病毒互补 DNA 物种的积累。在这里，我们表明，晚期 HIV-1 辅助蛋白 Vpu 劫持 DNA 修复机制，以促进在已经有效感染的细胞中核病毒 cDNA 的降解。Vpu 通过与核孔处的 RanBP2-RanGAP1*SUMO1-Ubc9 SUMO E3 连接酶复合物相互作用来实现这一点，从而重新编程早幼粒细胞白血病蛋白核体并减少 Bloom 综合征蛋白的 SUMO 化，释放病毒 cDNA 的末端降解。同时，Vpu 抑制 RAD52 介导的病毒 cDNA 的同源修复，防止长末端重复单拷贝的死端环状形式的产生，并允许持续的核酶攻击。我们的结果确定 Vpu 为 DNA 修复机制的关键调节剂。我们表明，Bloom 综合征蛋白消除了核 HIV-1 cDNA，从而抑制了免疫感应和前病毒超整合。针对 DNA 修复的治疗可能有助于诱导抗病毒免疫并抑制补充潜伏 HIV 储库的前病毒整合。
