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

Abstract

A systematic 2001-2007 review of 142 chronic fatigue syndrome (CFS) patients identified 106 CFS patients with elevated serum IgG antibodies to the herpesviruses EpsteinBarr virus (EBV), cytomegalovirus, or human herpesvirus (HHV) 6 in single or multiple infections, with no other co-infections detected. We named these 106 patients group-A CFS. Eighty-six of these 106 group-A CFS patients (81%) had elevated EBV early antibody, early antigen (diffuse), serum titers. A small group of six patients in the group-A EBV subset of CFS, additionally, had repetitive elevated-serum titers of antibody to the early lytic replicationencoded proteins, EBV dUTPase, and EBV DNA polymerase. The presence of these serum antibodies to EBV dUTPase and EBV DNA polymerase indicated EBV abortive lytic replication in these 6 CFS patients. None of 20 random control people (age-and sex-matched, with blood drawn at a commercial laboratory) had elevated serum titers of antibody to EBV dUTPase or EBV DNA polymerase (P , 0.01). This finding needs verification in a larger group of EBV CFS subset patients, but if corroborated, it may represent a molecular marker for diagnosing the EBV subset of CFS. We review evidence that EBV abortive lytic replication with unassembled viral proteins in the blood may be the same in infectious mononucleosis (IM) and a subset of CFS. EBV-abortive lytic replication in tonsil plasma cells is dominant in IM. No complete lytic virion is in the blood of IM or CFS patients. Complications of CFS and IM include cardiomyopathy and encephalopathy. Circulating abortive lytic-encoded EBV proteins (eg, EBV dUTPase, EBV DNA polymerase, and others) may be common to IM and CFS. The intensity and duration of the circulating EBV-encoded proteins might differentiate the IM and EBV subsets of CFS. Abortive lytic replication may be a pathogenic mechanism for EBV disease. EBV (HHV4) is a gamma herpesvirus composed of dsDNA about 170 Kb in length. For this discussion, there are early genes (including expressions of encoded proteins EBV dUTPase, DNA polymerase, and nuclear proteins) and late genes (including expressions of capsid and membrane proteins). Abortive infection infers incomplete virion expressions of either early or late proteins, but the virion is incomplete. The lytic virus infers a complete virion. The pathologic consequences of EBV abortive replication are currently being investigated by authors.

One-Year Follow-up of Young People with ME/CFS Following Infectious Mononucleosis by Epstein-Barr Virus

“…These findings were in line with previous research that has not found a distinct pattern of EBV-specific routine virological results in ME/CFS patients [42,102]. However, findings regarding EBV-specific immune responses in patients with ME/CFS are inconsistent, and EBV antigen mimicry might well contribute to pathogenic autoimmunity as shown by us in more comprehensive EBV-specific immunological analyses [35,44,46,[103][104][105][106][107]. EBV and herpes viruses in general have been discussed as a cause or perpetuating factor of ME/CFS, while no stringent causal association has been proven yet [41,42,102].…”

Surveying the Metabolic and Dysfunctional Profiles of T Cells and NK Cells in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

“…ME/CFS is often preceded by flu-like symptoms, and many patient accounts describe a viral-like illness or an identified infection around the time of onset [3]. Although the root cause of this condition is still uncertain, numerous studies have linked ME/CFS to viruses [7,8,[10][11][12][13][14][15][16]. However, identifying the specific virus responsible for the development of ME/CFS has proven to be a difficult challenge.…”

“…Despite this illness presentation, and other significant reports implying the involvement of an infectious event, the triggering agent remains a topic of debate in the scientific community [7][8][9][10]. Several viruses have been implicated in ME/CFS, including, but not limited to, the Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6), and enteroviruses A and B (EV-A and EV-B) [7,8,[10][11][12][13][14][15][16]. While the mechanisms by which one or more of these viruses may contribute to the development of ME/CFS are not fully understood, other studies indicate that chronic viral infections can cause long-term changes in the immune system [17] that are similar to those observed in ME/CFS.…”

Advancing Research and Treatment: An Overview of Clinical Trials in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Future Perspectives

“…VACV has improved GI absorption and is three times more orally bioavailable than ACV [25,26]. Two pilot studies found administering VACV over six months improved physical activity in ME/CFS patients with elevated EBV antibodies [29,30]. However, patients with elevated HCMV antibodies did not improve [29].…”