A paradigm linking herpesvirus immediate-early gene expression apoptosis and myalgic encephalomyelitis chronic fatigue syndrome

Abstract

There is no accepted science to relate herpesviruses (Epstein-Barr virus [EBV], human cytomegalovirus [HCMV], and human herpesvirus 6 [HHV6]) as causes of myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS). ME/CFS patients have elevated serum immunoglobulin (Ig)G serum antibody titers to EBV, HCMV, and HHV6, but there is no herpesvirus DNA-emia, herpesvirus antigenemia, or uniformly elevated IgM serum antibody titers to the complete virions. We propose that herpesvirus EBV, HCMV, and HHV6 immediate-early gene expression in ME/CFS patients leads to host cell dysregulation and host cell apoptosis without lytic herpesvirus replication. Specific antiviral nucleosides, which alleviate ME/CFS, namely valacyclovir for EBV ME/CFS and valganciclovir for HCMV/ HHV6 ME/CFS, inhibit herpesvirus DNA polymerases and/or thymidine kinase functions, thus inhibiting lytic virus replication. New host cell recruitment thus ceases. In the absence of new herpesvirus, nonpermissive herpesvirus replication stops, and ME/CFS recovery ensues.

Abortive lytic Epstein–Barr virus replication in tonsil-B lymphocytes in infectious mononucleosis and a subset of the chronic fatigue syndrome

“…12 EBV latent replication is not interrupted. 39 Valacyclovir levels in serum at this dosage (14.3 mg/kg q 6 hours) reach anti-EBV inhibitory concentrations of 22 µm (IC 50 EBV, 4.4-13.3 µm).…”

“…39 The in vitro and animal model studies of Glaser et al 53,54 suggest abortive lytic replication may be critical to IM and CFS; short-term acyclovir therapy has been unsuccessful. 52 This CFS diagnostic panel (used here) was not available in earlier studies.…”

“…24,37,38 An elevated serum IgG antibody to the structural protein EBV viral capsid antigen (VCA) with a concomitant negative IgM VCA EBV serum antibody records past infection. 39 Nevertheless, healthy people intermittently shed EBV infectious virus in their saliva. 30,31 Quantitative studies of EBV replication during IM indicate lytic replication in the tonsils is in the minority, and abortive lytic replication is dominant.…”

Herpesviruses dUTPases: A New Family of Pathogen-Associated Molecular Pattern (PAMP) Proteins with Implications for Human Disease

“…The hypothesis that reactivation of multiple herpesviruses may be involved with ME/CFS is supported by clinical studies demonstrating improvement of symptomology in a subset of patients following long-term therapy with valganciclovir, a potent inhibitor of herpesvirus replication, and relapse upon discontinuation of treatment [97,98,99,100]. Further support for a possible involvement of EBV in a subset of patients with ME/CFS comes from studies that reported improvement of symptoms following single treatment and maintenance therapy with Rituximab, an anti-CD20 antibody that effectively depletes B cells but not plasma cells [101,102,103].…”

Antibody to Epstein-Barr Virus Deoxyuridine Triphosphate Nucleotidohydrolase and Deoxyribonucleotide Polymerase in a Chronic Fatigue Syndrome Subset

“…Since valacyclovir and valganciclovir do not inhibit the synthesis of early herpesvirus proteins, thus inducing a type of abortive-lytic replication, we suggested that new herpesvirus host cell recruitment is interrupted in the CFS patients treated with valacyclovir/valganciclovir who recovered their health [16]. It is possible that one or more herpesvirus early proteins may be important to CFS pathophysiology.…”