Viruses with broad tissue distribution and cell tropism successfully replicate in various nutrient environments in the body. Several viruses reprogram metabolism for viral replication. However, many studies focus on metabolic reprogramming in nutrient-rich conditions that do not recapitulate physiological environments in the body. Here, we investigated how viruses may replicate when a metabolite thought to be essential for replication is limited. We use human cytomegalovirus infection in glucose-free conditions as a model to determine how glucose supports virus replication and how physiologically relevant nutrients contribute to glucose-independent virus production. We find that glucose supports viral genome synthesis, viral protein production and glycosylation, and infectious virus production. Notably, supplement of glucose-free cultures with uridine, ribose, or UDP-GlcNAc—metabolites that feed upper glycolytic branches like the pentose phosphate pathway—results in partially restored virus replication, including low levels of infectious virus production. Supplementing lower glycolysis in glucose-free cultures using pyruvate fails to restore virus replication. These results indicate that nutrients can compensate for glucose via feeding upper glycolytic branches to sustain low levels of virus production. More broadly, our findings suggest that viruses may successfully replicate in diverse metabolic niches, including those in the body with low glucose levels, through alternative nutrient usage.

中文翻译：

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葡萄糖非依赖性人巨细胞病毒复制由为上糖酵解分支提供营养的代谢物支持


具有广泛组织分布和细胞嗜性的病毒在体内的各种营养环境中成功复制。几种病毒对新陈代谢进行重编程以进行病毒复制。然而，许多研究集中在营养丰富的条件下的代谢重编程，而这些条件并不能概括体内的生理环境。在这里，我们研究了当被认为对复制至关重要的代谢物有限时病毒如何复制。我们使用无葡萄糖条件下的人类巨细胞病毒感染作为模型来确定葡萄糖如何支持病毒复制以及生理相关营养物质如何促进葡萄糖非依赖性病毒的产生。我们发现葡萄糖支持病毒基因组合成、病毒蛋白产生和糖基化以及感染性病毒产生。值得注意的是，在无葡萄糖培养物中补充尿苷、核糖或 UDP-GlcNAc（为磷酸戊糖途径等上糖酵解分支提供营养的代谢物）会导致病毒复制部分恢复，包括传染性病毒产生水平低。使用丙酮酸在无葡萄糖培养物中补充较低的糖酵解无法恢复病毒复制。这些结果表明，营养物质可以通过喂养上糖酵解分支来补偿葡萄糖，以维持低水平的病毒产生。更广泛地说，我们的研究结果表明，病毒可以通过替代营养素的使用成功地在不同的代谢生态位中复制，包括那些在低葡萄糖水平的体内的代谢生态位。