Immune evasion and inhibition of apoptosis are required for successful virus infection. However, inhibition of apoptosis can increase antiviral immune responses, which can then clear viral infections. Here we show that human cytomegalovirus (HCMV)-encoded UL37 exon-1 protein (UL37x1) not only inhibits apoptosis but also suppresses the cGAS-STING immune pathway. Using co-immunoprecipitation assays, we found that UL37x1 binds to TBK1 to abrogate the TBK1-STING-IRF3 interaction. Although the anti-apoptosis function of UL37x1 increases immune signalling, the immunosuppressive role of UL37x1 counteracts this undesirable side-effect. Furthermore, we used mutational analyses to show that the loss of either immunosuppressive or anti-apoptotic function of UL37x1 significantly reduced HCMV replication in human primary foreskin fibroblasts and humanized mice by over twofold. Finally, loss of both functions resulted in over fourfold reduction of HCMV replication in the same cell type and mouse model, showing that both UL37x1 functions are crucial for HCMV infection. We conclude that this sophisticated mechanism enables HCMV to control innate immunity and apoptosis to ensure efficient infection.

成功的病毒感染需要免疫逃避和细胞凋亡的抑制。然而，抑制细胞凋亡可以增加抗病毒免疫反应，从而清除病毒感染。在这里，我们显示人类巨细胞病毒 (HCMV) 编码的 UL37 外显子 1 蛋白 (UL37x1) 不仅抑制细胞凋亡，而且抑制 cGAS-STING 免疫途径。使用免疫共沉淀分析，我们发现 UL37x1 与 TBK1 结合以消除 TBK1-STING-IRF3 相互作用。虽然 UL37x1 的抗细胞凋亡功能增加了免疫信号，但 UL37x1 的免疫抑制作用抵消了这种不良副作用。此外，我们使用突变分析表明，UL37x1 的免疫抑制或抗凋亡功能的丧失显着降低了人类原代包皮成纤维细胞和人源化小鼠中 HCMV 复制的两倍以上。最后，这两种功能的丧失导致相同细胞类型和小鼠模型中 HCMV 复制减少四倍以上，表明两种 UL37x1 功能对 HCMV 感染至关重要。我们得出结论，这种复杂的机制使 HCMV 能够控制先天免疫和细胞凋亡，以确保有效感染。