Human herpesvirus 6A promotes glycolysis in infected T cells by activation of mTOR signaling

PLoS Pathog. 2020 Jun 9;16(6):e1008568. doi: 10.1371/journal.ppat.1008568. eCollection 2020 Jun.

Abstract

Human herpesvirus 6 (HHV-6) is an important immunosuppressive and immunomodulatory virus worldwide. However, whether and how HHV-6 infection influences the metabolic machinery of the host cell to provide the energy and biosynthetic resources for virus propagation remains unknown. In this study, we identified that HHV-6A infection promotes glucose metabolism in infected T cells, resulting in elevated glycolytic activity with an increase of glucose uptake, glucose consumption and lactate secretion. Furthermore, we explored the mechanisms involved in HHV-6A-mediated glycolytic activation in the infected T cells. We found increased expressions of the key glucose transporters and glycolytic enzymes in HHV-6A-infected T cells. In addition, HHV-6A infection dramatically activated AKT-mTORC1 signaling in the infected T cells and pharmacological inhibition of mTORC1 blocked HHV-6A-mediated glycolytic activation. We also found that direct inhibition of glycolysis by 2-Deoxy-D-glucose (2-DG) or inhibition of mTORC1 activity in HHV-6A-infected T cells effectively reduced HHV-6 DNA replication, protein synthesis and virion production. These results not only reveal the mechanism of how HHV-6 infection affects host cell metabolism, but also suggest that targeting the metabolic pathway could be a new avenue for HHV-6 therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • DNA Replication / drug effects
  • DNA, Viral / biosynthesis
  • Deoxyglucose / pharmacology
  • Glucose / metabolism
  • Glycolysis*
  • Herpesvirus 6, Human / metabolism*
  • Humans
  • Lactic Acid / metabolism
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Roseolovirus Infections / drug therapy
  • Roseolovirus Infections / metabolism*
  • Roseolovirus Infections / pathology
  • Signal Transduction*
  • T-Lymphocytes / metabolism*
  • T-Lymphocytes / pathology
  • T-Lymphocytes / virology
  • TOR Serine-Threonine Kinases / metabolism*
  • Viral Proteins / biosynthesis
  • Virion / metabolism

Substances

  • DNA, Viral
  • Viral Proteins
  • Lactic Acid
  • Deoxyglucose
  • MTOR protein, human
  • Mechanistic Target of Rapamycin Complex 1
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • Glucose

Grants and funding

This work was supported by the National Natural Science Foundation of China (grants 81571979 to HT, 81201520 to LL and 81273235 to KY), the plan of Jiangsu Innovative and Entrepreneurial team (303073227 to HT) and the Natural Science Foundation of Jiangsu Province of China (grant BK20171489 to LL). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.