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

Huamin Tang,Philip E Pellett,Junli Jia,Zhisheng Wu,Lingyun Li,Jingjing Ma,Kun Yao,Guangyong Peng,Xianyi Xu,Jialin Yao,Xuefeng Jiang,Mengyuan Xu

doi:10.1371/journal.ppat.1008568

Huamin Tang, Philip E Pellett + Show 10 more

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https://doi.org/10.1371/journal.ppat.1008568

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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.

Highlights

Human herpesvirus 6 (HHV-6) is a ubiquitous pathogen of the betaherpesvirinae family, with a nearly 90% seroprevalence rate in healthy adults[1, 2]
In the study presented here, we have demonstrated that HHV-6A infection promotes glucose metabolism in infected T cells
Further exploration into the mechanism demonstrated that HHV-6A infection increases the expressions of the key glucose transporters and glycolytic enzymes, as well as activates the AKTmTORC1 signaling, which is involved in HHV-6A-induced glycolysis activation in HHV6-infected T cells

Summary

Introduction

Human herpesvirus 6 (HHV-6) is a ubiquitous pathogen of the betaherpesvirinae family, with a nearly 90% seroprevalence rate in healthy adults[1, 2]. HHV-6 has been classified into two distinct species, HHV-6A and HHV-6B, with significant differences in their biological, immunological, and pathogenic characteristics[5, 6]. Reactivation of HHV-6B frequently occurs in immunocompromised patients such as solid organ or hematopoietic stem cell transplant recipients. HHV-6 reactivation in transplant recipients is associated with poor outcomes, including acute graft-versus-host disease (GVHD), pneumonia, delayed engraftment, as well as lethal encephalitis[8, 9]. Several studies suggest HHV-6A might be involved in other pathologies, such as multiple sclerosis[10], Hashimoto’s thyroiditis[11, 12], the Alzheimer’s disease[13] and glioma[14]

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