Human Herpesvirus-6 Reactivation, Mitochondrial Fragmentation, and the Coordination of Antiviral and Metabolic Phenotypes in Myalgic  Encephalomyelitis/Chronic Fatigue Syndrome.

Abstract

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multifactorial disorder with many possible triggers. Human herpesvirus (HHV)-6 and HHV-7 are two  infectious triggers for which evidence has been growing. To understand possible  causative role of HHV-6 in ME/CFS, metabolic and antiviral phenotypes of U2-OS  cells were studied with and without chromosomally integrated HHV-6 and with or  without virus reactivation using the histone deacetylase inhibitor  trichostatin-A. Proteomic analysis was conducted by pulsed stable isotope  labeling by amino acids in cell culture analysis. Antiviral properties that were  induced by HHV-6 transactivation were studied in virus-naive A549 cells  challenged by infection with influenza-A (H1N1) or HSV-1. Mitochondria were  fragmented and 1-carbon metabolism, dUTPase, and thymidylate synthase were  strongly induced by HHV-6 reactivation, whereas superoxide dismutase 2 and  proteins required for mitochondrial oxidation of fatty acid, amino acid, and  glucose metabolism, including pyruvate dehydrogenase, were strongly inhibited.  Adoptive transfer of U2-OS cell supernatants after reactivation of HHV-6A led to  an antiviral state in A549 cells that prevented superinfection with influenza-A  and HSV-1. Adoptive transfer of serum from 10 patients with ME/CFS produced a  similar fragmentation of mitochondria and the associated antiviral state in the  A549 cell assay. In conclusion, HHV-6 reactivation in ME/CFS patients activates a  multisystem, proinflammatory, cell danger response that protects against certain  RNA and DNA virus infections but comes at the cost of mitochondrial fragmentation  and severely compromised energy metabolism.