Metabolites that feed upper glycolytic branches support glucose independent human cytomegalovirus replication.

The metabolic environment is a determinant in the ability of a virus to successfully replicate. HCMV has broad cell tropism and replicates in various tissues that have diverse and/or limiting metabolic environments. We know that HCMV reprograms host central carbon metabolism to support viral replication, but we have little understanding of HCMV replication in diverse metabolic niches as most studies use high nutrient culture media. Here, we show that glucose limitation suppresses virus production through loss of viral genome synthesis and viral protein glycosylation. However, nutrient compensation by uridine, ribose, and UDP-GlcNAc, metabolites that fuel upper glycolytic branches such as the non-oxidative pentose phosphate pathway support low levels of glucose-independent virus production. Our work indicates that metabolite compensation may facilitate HCMV replication in nutrient limited niches in the body.