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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. Author summary: Human herpesvirus 6 (HHV-6) is a member of the betaherpesvirinae family, which primarily infects T lymphocytes. 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 AKT-mTORC1 signaling, which is involved in HHV-6A-induced glycolysis activation in HHV-6-infected T cells. Importantly, suppression of glycolysis or mTORC1 activity effectively reduced HHV-6A propagation. Therefore, recognition of the effects of HHV-6 on host cell metabolism will not only facilitate a better understanding of viral pathogenesis but also could reveal potential therapeutic targets for HHV-6-associated diseases by metabolic manipulation. [ABSTRACT FROM AUTHOR]

AMP-activated protein kinase (AMPK) is a cellular energy sensor regulating metabolic homeostasis. In this study, we investigated the role of AMPK in response to human herpesvirus 6A (HHV-6A) infection. We show that HHV-6A infection significantly downregulates the active phosphorylated state of AMPK in infected T cells. Pharmacological activation of AMPK highly attenuated HHV-6A propagation. Mechanistically, we found that the activation of AMPK by AICAR blocked HHV-6-induced glycolysis by inhibiting glucose metabolism and lactate secretion, as well as decreasing expressions of key glucose transporters and glycolytic enzymes. In addition, mTOR signaling has been inactivated in HHV-6A infected T cells by AICAR treatment. We also showed that HHV-6A infection of human umbilical cord blood mononuclear cells (CBMCs) reduced AMPK activity whereas the activation of AMPK by metformin drastically reduced HHV-6A DNA replication and virions production. Taken together, this study demonstrates that AMPK is a promising antiviral therapeutic target against HHV-6A infection. • HHV-6A infection inhibits AMPK activity in infected T cells. • Pharmacological activation of AMPK reduces HHV-6A replication. • Activation of AMPK by AICAR blocks HHV-6-induced glycolysis and mTOR signaling. • AMPK is a promising antiviral therapeutic target against HHV-6A infection. [ABSTRACT FROM AUTHOR]

Abstract: Human herpesvirus 6 (HHV-6), which replicates abundantly in T cells, belongs to the Roseolovirus genus within the betaherpesvirus subfamily. Members of the Roseolovirus genus encode seven unique genes, U20, U21, U23, U24, U24A, U26, and U100. The present study focused on one of these, U23, by analyzing the characteristics of its gene product in HHV-6A-infected cells. The results indicated that the U23 protein was expressed at the late phase of infection as a glycoprotein, but was not incorporated into virions, and mostly stayed within the trans Golgi network (TGN) in HHV-6A-infected cells. Furthermore, analysis using a U23-defective mutant virus showed that the gene is nonessential for viral replication in vitro. [Copyright &y& Elsevier]

Human herpesvirus 6 is a T lymphotropic herpesvirus, long classified into variants A and B (HHV-6A and HHV-6B) based on differences in sequence and pathogenicity. Recently, however, HHV-6A and HHV-6B were reclassified as different species. Here, we isolated a neutralizing monoclonal antibody (Mab) named AgQ 1-1 that was specific for HHV-6A glycoprotein Q1 (AgQl), and we showed that amino acid residues 494 to 497 of AgQl were critical for its recognition by this Mab. This region was also essential for AgQl's complex formation with gH, gL, and gQ2, which might be important for viral binding to the cellular receptor, CD46. In addition, amino acid residues 494 to 497 are essential for viral replication. Interestingly, this sequence corresponds to the domain on HHV-6B gQl that is critical for recognition by an HHV-6B-specific neutralizing Mab. Within this domain, only Q at position 496 of HHV-6A is distinct from the HHV-6B sequence; however, the mutant AgQl (Q496E) was still clearly recognized by the Mab AgQ 1 -1. Surprisingly, replacement of the adjacent amino acid, in mutant AgQ 1 (C495A), resulted in poor recognition by Mab AgQ 1-1, and AgQl(C495A) could not form the gH/gL/gQl/gQ2 complex. Furthermore, the binding ability of mutant AgQl (L494A) with CD46 decreased, although it could form the gH/gL/gQl/gQ2 complex and it showed clear reactivity to Mab AgQ 1 -1. These data indicated that amino acid residues 494 to 497 of AgQl were critical for the recognition by Mab AgQ 1-1 and essential for AgQl's functional conformation. [ABSTRACT FROM AUTHOR]

Human herpesvirus 6 (HHV-6) is a T cell-tropic betaherpesvirus. HHV-6 can be classified into two variants, HHV-6A and HHV-6B, based on differences in their genetic, antigenic, and growth characteristics and cell tropisms. The function of HHV-6B should be analyzed more in its life cycle, as more than 90% of people have the antibodies for HHV-6B but not HHV-6A. It has been shown that the cellular receptor for HHV-6A is human CD46 and that the viral ligand for CD46 is the envelope glycoprotein complex gH/gL/gQ1/gQ2; however, the receptor-ligand pair used by HHV-6B is still unknown. In this study, to identify the glycoprotein(s) important for HHV-6B entry, we generated monoclonal antibodies (MAbs) that inhibit infection by HHV-6B. Most of these MAbs were found to recognize gQ1, indicating that HHV-6B gQ1 is critical for virus entry. Interestingly, the recognition of gQ1 by the neutralizing MAb was enhanced by coexpression with gQ2. Moreover, gQ1 deletion or point mutants that are not recognized by the MAb could nonetheless associate with gQ2, indicating that although the MAb recognized the conformational epitope of gQ1 exposed by the gQ2 interaction, this epitope was not related to the gQ2 binding domain. Our study shows that HHV-6B gQ1 is likely a ligand for the HHV- 6B receptor, and the recognition site for this MAb will be a promising target for antiviral agents. [ABSTRACT FROM AUTHOR]