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Impact of Diverse Nutrient Environment on Viral Replication and Metabolite Flow in Human Cytomegalovirus Infection

Sponsored by National Institute of Allergy and Infectious Disease

$69.1K Funding
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Project Abstract Human cytomegalovirus (HCMV) is a prevalent herpesvirus that establishes lifelong infection. HCMVinfection causes severe disease in immunocompromised individuals and is a leading cause of congenitaldisabilities. Like all viruses HCMV relies on host metabolism for the building blocks of viral replication such asnucleotides for viral genome synthesis amino acids for viral proteins and lipids for the virus membrane. HCMVis highly species-specific which limits molecular investigation of virus replication to cell culture models ofinfection. Prior research on HCMV metabolic remodeling of host metabolism utilized high nutrient culture mediawith a focus on obtaining optimal virus production. However high nutrient media that supports optimal virusreplication does not recapitulate the nutrient environment in the human body. This project will address thisdrawback by identifying how low nutrient environments alter nutrient utilization to support HCMV replication. Ihypothesize that HCMV can replicate to sub-optimal levels in diverse nutrient environments via metabolicflexibility. I am initiating these studies by focusing on glucose utilization and alternative nutrient flow in glucose-freecultures during HCMV infection. Preliminary data demonstrate that viral genome synthesis viral protein levelsand virus production are decreased during glucose deprivation. Rescuing viral genome levels does not restorevirus production suggesting that glucose supports multiple steps of virus replication. While lipids are normallymade from glucose during HCMV replication I found that lipids are synthesized during HCMV infection despitethe loss of glucose suggesting that alternative nutrient flow is occurring. In aim 1 I will determine how glucoseloss impacts HCMV replication stages. These studies will define the stages of virus replication that requireglucose and will determine which nutrients can compensate for glucose to support virus replication. In aim 2 Iwill identify how glucose loss alters nutrient flow to support lipid synthesis during HCMV replication. This workwill determine if glutamine is compensating for glucose for lipid synthesis and investigate how glucose levelsimpact nutrient flow. These studies build upon prior research that identified the complexities of HCMV metaboliccontrol. The resulting discoveries will increase our understanding of metabolic remodeling and alternativenutrient use during HCMV replication while providing insight for developing a more physiological-relevant modelof HCMV interaction with host metabolism.