- Open Access
Chronic viral infections in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)
© The Author(s) 2018
- Received: 2 August 2018
- Accepted: 24 September 2018
- Published: 1 October 2018
Background and main text
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex and controversial clinical condition without having established causative factors. Increasing numbers of cases during past decade have created awareness among patients as well as healthcare professionals. Chronic viral infection as a cause of ME/CFS has long been debated. However, lack of large studies involving well-designed patient groups and validated experimental set ups have hindered our knowledge about this disease. Moreover, recent developments regarding molecular mechanism of pathogenesis of various infectious agents cast doubts over validity of several of the past studies.
This review aims to compile all the studies done so far to investigate various viral agents that could be associated with ME/CFS. Furthermore, we suggest strategies to better design future studies on the role of viral infections in ME/CFS.
- Viral infections
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease that causes central nervous system (CNS) and immune system disturbances, cell energy metabolisms and ion transport dysfunction, as well as cardiovascular problems, gastrointestinal dysfunction, cognitive impairment, myalgia, arthralgia, orthostatic intolerance, inflammation and innate immunity disturbances. The main clinical sign is persisting chronic fatigue, which is not relieved by rest and lasts for more than 6 months . A large group of patients remains wheelchair-dependent and many remain housebound or even bedbound .
ME/CFS is sporadic with occasional outbreaks . Currently around 80% of ME/CFS cases are undiagnosed . According to the available literature, already back in 2009 around 17 million people were diagnosed with this disease, including 800,000 patients in the United States of America and 240,000 in the United Kingdom . Etiological factors for ME/CFS include genetic predisposition, stress, trauma, exposure to toxins, physical activity and rest ratio, as well as a recent history of infectious disease . Females within the age group of 30–39 years are more prone to this disease . Nevertheless, ME/CFS can affect individuals from all races, genders, age groups and social statuses. Population studies show that the prevalence of ME/CFS worldwide is from 0.2% of clinically diagnosed up to 3.48% of self-reported population depending on the applied diagnostic criteria. Most of the patients with ME/CFS suffer from long lasting symptoms, with only 6% of patients experiencing remission of the disease [7–9]. ME/CFS symptoms range from long lasting fatigue, memory loss, difficulty concentrating, sore throat, lymphadenopathy, muscle pain, headaches and un-refreshing sleep to extreme fatigue after exertion. The pathomechanisms of ME/CFS are still unknown, and there are no standardized biological markers or tests for diagnostics; therefore, even the existence of this medical diagnosis has been questioned for long time .
During the past 2 decades, few illnesses have been as extensively discussed as chronic fatigue syndrome (CFS). A consensus for the proper diagnostic definition for CFS was reached in 1994 on a case definition from the United States Centers for Disease Control and Prevention . Therefore, prolonged fatigue is defined as self-reported, persistent fatigue lasting 1 month whereas chronic fatigue is persistent or relapsing fatigue lasting 6 months or longer . Later in 2011 International Consensus Panel (ICP) developed International Consensus Criteria suggesting that this disease is to be defined as myalgic encephalomyelitis (ME) due to neuropathological inflammation .
Clinical evaluation for identifying underlying or contributing conditions of chronic fatigue is required before further diagnosis or classifications can be made. Besides persistent post-exertional fatigue, ME/CFS is characterized by substantial symptoms related to cognitive, immune and autonomous dysfunctions [13, 14]. Though ME/CFS is a chronic illness of uncertain cause with unknown pathogenesis, there is abundant evidence of an underlying biological process. Since sudden disease outbreaks in patients start with a “flu-like” illness, it seems plausible that an infectious agent can trigger the syndrome. In fact, viral-like illnesses appear to precede ME/CFS onset in approximately 50% of patients . In addition, there are indications that immunological dysfunction may contribute to the emergence of symptoms .
The pathogenesis of ME/CFS is likely multi-factorial and various microbial and viral infections are considered to be the possible trigger factors of ME/CFS. The illness has been frequently accompanied with various viral infections and studies have been conducted on association of ME/CFS with Epstein–Barr virus (EBV) [17, 18], cytomegalovirus (CMV) , human herpesvirus (HHV) 6, HHV-7, HHV-8 [20–22], human parvovirus B19 (B19V), enteroviruses , lentivirus  and bacteria as mycoplasma , Lyme disease causing borrelia, Q fever causing Coxiella burnetii  and other pathogens.
Still, the association of ME/CFS with a single infectious agent has not been confirmed, and the role of viral infections in ME/CFS remains obscure [2, 27]. This may be attributed to the small size and/or heterogeneity of studied ME/CFS populations, not well-characterized ME/CFS patients, lack of adequate controls, high prevalence of persistent viral infection in the general population, different methodological approaches applied and so on. Here we present an overview of studies addressing the possible association of viral infections with ME/CFS, focusing on human herpesviruses, B19V, and enteroviruses, which all can trigger ME/CFS. These viruses, after an acute infection, remain in the body as mostly latent, persistent infections and may reactivate under various conditions. Immunologic disturbance associated with ME/CFS may be the result of viral infection or may lead to reactivation of latent viruses. Once reactivated, the viruses may contribute to the morbidity of ME/CFS via inflammation and immune dysregulation, especially the herpesviruses EBV and HHV-6, which infect immune cells . Viral infections can trigger an autoimmune response as well . In the majority of ME/CFS cases, there is no conclusive evidence for chronic viral infection, but it is plausible that viruses could act via a “hit and run” mechanism; this theory proposes that viruses trigger the disease, cause immune abnormalities and leave a dysfunctional immune system and/or autoimmunity.
According to the International Committee on Taxonomy of Viruses, Herpesviridae family includes Alphaherpesvirinae, Betaherpesvirinae and Gammaherpesvirinae subfamilies. Currently there are nine human herpesviruses: herpes simplex virus (HSV)-1, HSV-2, varicella zoster virus (VZV), EBV, CMV, HHV-6A, HHV-6B, HHV-7, HHV-8. HHV-6 and HHV-7, members of the Herpesviridae family, Beta-herpesvirinae subfamily, Roseolovirus genus, are most studied human pathogens in association with ME/CFS . HHV-6A was first isolated in 1986 from peripheral blood mononuclear cells (PBMCs) of patients with acquired immunodeficiency syndrome (AIDS) and lympholeukosis . HHV-7 was first isolated in 1990 from CD4+ lymphocytes of healthy adult . Primary infection with these viruses usually is observed in early childhood—from age of 6 months to 3 years. They can cause Roseola infantum or Exanthema subitum with fever, rashes and elevated body temperature lasting for 3 to 5 days. In addition, it can affect several organ systems, including CNS . Likewise, infection course can be asymptomatic . HHV-6B and HHV-7 are widespread and prevalence is more than 90% of general population . The seroprevalence of HHV-6A is unknown. However one study of Chinese individuals put the prevalence at 11% of controls . One feature of all herpesviruses is that they can establish a lifelong persistent infection termed latency . Latent HHV-6 can reside in a dormant state inside human host cells by integrating viral genome into telomeric ends of host cell chromosomes (ciHHV-6) . Recently also chromosomal integration of HHV-7 into the host genome was discovered . During latency, minimal viral transcription and no production of infectious virions occurs, resulting in no detectable clinical complications. However, activated forms of HHV-6A/B and HHV-7 are known to have immunomodulating properties such as modulating the expression of several cytokines and chemokines or inducing immunosuppression by triggering apoptosis in lymphocytes [40–42]. Since both viruses are ubiquitous, concurrent infection is common and it has also been reported, that HHV-7 can reactivate HHV-6A/B [43–45].
Reactivation of latent HHV-6A/B can be caused by various stress conditions leading to increased severities of multiple human disorders [46, 47]. Even though evidence is lacking, it is also possible that exposure to certain drugs could reactive ciHHV-6. One known chemical to reactivate HHV-6 in vitro is the HDAC inhibitor Trichostatin A . Similarly two other commonly known pharmaceuticals, sodium valporate and amoxicillin, also enhance HHV-6 replication [49, 50]. Virus reactivation is possible in cases of immune disturbances, long-term stress, immunosuppressive therapy, prolonged anaesthesia, transplantation, AIDS and others . For example, HHV-6A reactivation has been found in patients with multiple sclerosis (MS)  and HIV infection  and HHV-6B reactivation has occurred in amnesia  and hepatitis . The virus can also reactivate in the presence of malignant and non-malignant diseases  and HHV-6A antibodies are a risk factor for non-Hodgkin lymphoma .
Due to its life-long persistence and its broad tissue tropism, HHV-6 has been speculated to be a possible trigger for ME/CFS. The involvement of herpesviruses in ME/CFS was already considered in 1988, when serological evidence pointed to reactivation of HHV-6 among patients, and a subset of patients were found to exhibit higher levels of antibodies against the EBV viral capsid antigen (VCA) and early antigen (EA) but an absence of antibodies to EBNA . Based on earlier reports and presentations, Ablashi suggested in 1994 that ME/CFS could be a result of immunological disturbances after herpesvirus reactivation . Investigating this hypothesis, Buchwald et al. started the first large study , when the case definition for ME/CFS had not yet been made. Their study included 259 patients with ME/CFS symptoms. Serum chemistry tests and polymerase chain reaction (PCR) assays confirmed the finding of active HHV-6 infection in 70% of patients. Even though they suggested that active replication of HHV-6 represented reactivation of latent infection due to immunologic dysfunction, they did not directly address HHV-6 playing a role in producing ME/CFS symptoms.
Follow-up studies using only serological techniques could not differentiate between active and latent infection [21, 22] but revealed a slight tendency to an association between ME/CFS and HHV-6, with a greater prevalence and higher levels of HHV-6-specific antibodies in patients, as well as a greater prevalence of DNA in PBMCs from those with ME/CFS. Notably, in both of these studies, HHV-6A was found to predominate among ME/CFS patients. Moreover, an association between active HHV-6 infection and ME/CFS has been demonstrated in studies distinguishing between active and latent infection using immunofluorescence assays directed against HHV-6A antigens or early antibody assays [58, 59]. On the other hand, there are several studies in which both serological techniques as well as PCR-based techniques distinguishing between active and latent infection lead to the conclusion that HHV-6 infection does not correlate with ME/CFS [60, 61]. Chapenko et al.  also evaluated whether HHV-6 infections could be the causative agent for ME/CFS. They found active HHV-6 more often in ME/CFS patients than controls, and active infection correlated with the occurrence of the clinical symptoms of ME/CFS, including lymphadenopathy, subfebrility, and malaise after exertion.
The presence of HHV-7 and other HHVs has been determined in patients with ME/CFS. Sairenji et al. revealed 100% HHV-7 seropositivity among 20 patients . In another study involving 17 ME/CFS patients, HHV-7 reactivation was detected more frequently than HHV-6 reactivation and concurrent active HHV-6 and HHV-7 infection was accompanied by immunological changes in the form of significantly increased CD95+ cells, decreased CD3+ and CD4+ T cells, and a lower CD4/CD8 ratio . Active HHV-6, HHV-7 and B19V infection/co-infection was confirmed analysing 108 patients with ME/CFS .
However, PCR analysis showed a similarly high detection rate of HHV-7 genomic sequences among patients with ME/CFS and controls (82% vs 83%) . In another study, the percentage of HHV-6, HHV-7 and co-infection was similar between patients and controls; nevertheless, HHV-7 was approximately two times more prevalent than HHV-6, with HHV-6 and HHV-7 DNA detected in the PBMCs of 26.7% and 69.9% of healthy adults, respectively, and 35.1% and 77.3% of ME/CFS patients . Others found HHV-7 DNA in only 7.7% of peripheral blood lymphocyte samples from patients with ME/CFS using PCR . In addition, detection of HHV-7 in a high percentage of gastro-intestinal biopsies from patients (85–92%) and controls (66–83%) with quantitative PCR (qPCR) is reported, though without statistical difference between the groups . No difference between severity of symptoms and viral load of HHV-6 and HHV-7 in saliva and PBMC of ME/CFS patients and controls was shown . Besides, detectable reactivation of HHV-6A/6B and HHV-7 in saliva is considered as a biomarker for physiological fatigue, and can therefore be used to distinguish between pathological and physiological fatigue .
Publications on analysis of human herpesvirus 6 and/or 7 in myalgic encephalomyelitis/chronic fatigue syndrome
HHV-6 reactivation in chronic fatigue syndrome
Josephs et al.
7 patients, 2 controls
IFA, Southern blot
A chronic illness characterized by fatigue, neurologic and immunologic disorders, and active human herpesvirus type 6 infection
Buchwald et al.
259 patients, 47 controls
Prevalence of human herpesvirus 6 variants A and B in patients with chronic fatigue syndrome
Yalcin et al.
13 patients, 13 controls
Antibody responses to Epstein–Barr virus, human herpesvirus 6 and human herpesvirus 7 in patients with chronic fatigue syndrome
Sairenji et al.
20 patients, 26 controls
Prevalence of IgM antibodies to human herpesvirus 6 early antigen (p41/38) in patients with chronic fatigue syndrome
Patnaik et al.
154 patients, 165 controls
Active HHV-6 infection in chronic fatigue syndrome patients from Italy: new data
Zorzenon et al.
52 patients, 51 controls
Frequent HHV-6 reactivation in multiple sclerosis (MS) and chronic fatigue syndrome (CFS) patients
Ablashi et al.
35 patients, 28 controls
Dynamics of chronic active herpesvirus-6 infection in patients with chronic fatigue syndrome: data acquisition for computer modeling
Krueger et al.
Activation of human herpesviruses 6 and 7 in patients with chronic fatigue syndrome
Chapenko et al.
17 patients, 12 patients with UCF, 20 controls
Plasma, serum, PBMCs
nPCR, flow cytometry
Association of active human herpesvirus-6, -7 and Parvovirus B19 infection with clinical outcomes in patients with myalgic encephalomyelitis/chronic fatigue syndrome
Chapenko et al.
108 patients, 90 controls
ELISA, nPCR, qPCR, REA
Myalgic encephalomyelitis/chronic fatigue syndrome and gulf war illness patients exhibit increased humoral responses to the herpesvirus-encoded dUTPase: implications in disease pathophysiology
Halpin et al.
74 patients, 151 controls
Human herpesvirus 6 and human herpesvirus 7 in chronic fatigue syndrome
Di Luca et al.
36 patients, 24 controls
No: HHV-7 Yes: HHV-6A
Chronic fatigue syndrome: clinical condition associated with immune activation
Landay et al.
63 patients, 40 controls
A comprehensive immunological analysis in chronic fatigue syndrome
Gupta , Vayuvegula
20 patients, 20 controls
Clinical, epidemiologic, and virologic studies in four clusters of the chronic fatigue syndrome
Levine et al.
31 patients, 105 controls
IFA, western blot, PCR
Simultaneous measurement of antibodies to Epstein–Barr virus, human herpesvirus 6, herpes simplex virus types 1 and 2, and 14 enteroviruses in chronic fatigue syndrome: is there evidence of activation of a nonspecific polyclonal immune response?
20 patients, 20 controls
Detection of human herpesvirus 6 in plasma of children with primary infection and immunosuppressed patients by polymerase chain reaction
Secchiero et al.
39 patients, 37 controls
Plasma or serum
Chronic fatigue syndrome (CFS): a critical evaluation of testing for active human herpesvirus-6 (HHV-6) infection
Wagner et al.
IFA, ELISA, nPCR
Viral serologies in patients with chronic fatigue and chronic fatigue syndrome
Buchwald et al.
548 patients (CFS, CF and FM), 30 controls
ELISA, western blot, IFA
Human herpesviruses in chronic fatigue syndrome
76 patients, 73 controls
Human herpesvirus 6 and 7 in chronic fatigue syndrome: a case–control study
Reeves et al.
26 patients, 50 controls
No evidence of active infection with human herpesvirus 6 (HHV-6) or HHV-8 in chronic fatigue syndrome
Enbom et al.
8 patients, 7 controls
Markers of viral infection in monozygotic twins discordant for chronic fatigue syndrome
Koelle et al.
11 patients, 11 controls
Plasma, PBMCs, serum
Multiple co-infections (mycoplasma, chlamydia, human herpesvirus-6) in blood of chronic fatigue syndrome patients: association with signs and symptoms
Nicolson et al.
204 patients, 100 controls
PCR, Southern blot
Detection of herpesviruses and parvovirus B19 in gastric and intestinal mucosa of chronic fatigue syndrome patients
Fremont et al.
48 patients, 35 controls
Gastro-intestinal biopsies, serum
Serological and virological investigation of the role of the herpesviruses EBV, CMV and HHV-6 in post-infective fatigue syndrome
Cameron et al.
20 patients, 10 controls
No serological evidence for a role of HHV-6 infection in chronic fatigue syndrome
Burbelo et al.
72 patients, 59 controls
Human endogenous retrovirus-K18 superantigen expression and human herpesvirus-6 and human herpesvirus-7 viral loads in chronic fatigue patients
Oakes et al.
39 patients, 9 controls
Human herpesvirus 6 and 7 are biomarkers for fatigue, which distinguish between physiological fatigue and pathological fatigue
Aoki et al.
97 patients, 113 controls
Several groups have also reported co-infections of EBV with HHV-6 in ME/CFS patients . Serological analysis has revealed a higher frequency of antibodies to EBV VCA in patients than controls. In addition, these serum antibodies could persist for several years, indicating that immune disturbances may allow viral reactivation . An abnormal immune response to EBV infection has been reported in ME/CFS cases; however, later publication showed no differences of EBV prevalence among patients and controls [72, 73]. Although Manian and colleagues found higher titers of IgG class antibodies against EBV viral capsid antigen in patients than in controls, they did not find a statistically significant difference in titers of antibodies to early antigens of EBV, HSV-1, HSV-2 and HHV-6 in patients compared to healthy controls. Therefore, they did not conclude that there was a significant association between these infections and ME/CFS . Elsewhere, ME/CFS patients’ EBV antibody titers were not significantly different compared to controls . In 1991, Landay et al. found antibodies to EBV early antigen significantly more frequently among ME/CFS patients than healthy adults, but they observed equal rates of EBV VCA and EBNA seropositivity among patients and controls . At the same time, other studies showed no correlation between EBV infection, nor CMV infection, and ME/CFS [77, 78]. A very low percentage of EBV-specific IgG class antibodies in patients and controls has been described . Zhang et al. have shown that EBV seroprevalence (VCA IgG) among ME/CFS patients was similar to that of the general population, but VCA IgM titers, EBNA IgG titers, and EBV-related genes were associated with ME/CFS subtypes . Moreover, in this cohort, most ME/CFS patients demonstrated primary infection/reactivation serostatus, while the serostatus of controls most often corresponded to the late phase of EBV infection.
In some reports, EBV was not detected in blood plasma by PCR , and no difference was revealed in the frequency of EBV genomic sequences detected in stomach and duodenum biopsies by qPCR . Likewise, other studies using immunofluorescence, enzyme-linked immunosorbent assay (ELISA), PCR and western blot have shown that EBV is present, though not significantly more often in patients with ME/CFS than in controls [81–84].
Recently published data also support the hypothesis on herpesviruses involvement in ME/CFS development due to expression of antibodies against herpesviruses-encoded deoxyuridine triphosphate nucleotidohydrolases (dUTPases) that activates humoral immune response ; anti-EBV and HHV-6 dUTPase antibodies were present in 55.4% and 54.06% of ME/CFS patients in one cohort, respectively. The same study found EBV dUTPase antibodies in 29.09% of patients and 25.83% of controls overall from a separate cohort. Compared to controls, the patients had significantly higher anti-EBV dUTPase antibodies.
Serum antibody and genomic sequence analysis of HSV, VZV, EBV, CMV, HHV-6, HHV-7, HHV-8, JC virus, BK virus, and B19V in 22 monozygotic twin pairs, of which one twin met criteria for ME/CFS and the other twin was healthy, revealed no differences between the group of twins with ME/CFS and the healthy twins . Similarly, Cameron and co-workers did not find significant differences in EBV, HHV-6, nor CMV seropositivity and viral loads between 20 ME/CFS patients and 10 controls using qPCR as well as serological assays for HHV-6 IgG, CMV IgM, and EBV IgG VCA p18, IgG EBNA-1, and IgG EA . Landay et al. also failed to find any serological links between these viruses as well as adenovirus, HTLV I/II, HIV, papovavirus, human spumavirus, rubeola, and coxsackie B4 and the pathogenesis of ME/CFS  Elevated IgG titers to CMV were demonstrated in only 6/107 (6%) patients with ME/CFS and only rarely were HSV, coxsackievirus, chlamydia, campylobacter, yersinia or candida infections observed . Likewise, serum analysis revealed no correlation between ME/CFS and CMV, HSV-1, HSV-2 and adenovirus in another report . However, analysis of more ME/CFS patients and controls showed the presence of CMV IgM p52 and CM2 antibodies in 16/34 patients and none of the controls, suggesting an etiologic role of CMV in ME/CFS . HHV-8, which has been infrequently studied in this disease, was found in 2/35 (5.7%) ME/CFS patients and in 1/25 (4%) controls .
Although an association of ME/CFS with viral infections has not been demonstrated in all studies, ME/CFS can be triggered by various factors, and infections could contribute to a subgroup of ME/CFS patients [66, 83]. Moreover, autoimmune, immune, metabolic and psychological disturbances could emerge due to infectious disease .
Single-stranded positive-sense RNA viruses from the Enterovirus genus belong to the Picornaviridae family. They comprise a large group of more than 70 different enteroviruses that have the ability to infect humans. Although enteroviral infections in humans are frequently asymptomatic, they can exert a variety of symptoms during acute infections. In addition, chronic enteroviral infections have been implicated in myocarditis [87–89] and in juvenile-onset type-1 diabetes .
Publications on analysis of enteroviruses in myalgic encephalomyelitis/chronic fatigue syndrome
Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with post-viral fatigue syndrome
Gow et al.
60 CFS, 41 controls
Persistence of enterovirus RNA in muscle biopsy samples suggests that some cases of chronic fatigue syndrome result from a previous, inflammatory viral myopathy
148 CFS, 152 controls
Simultaneous measurement of antibodies to Epstein–Barr virus, human herpesvirus 6, herpes simplex virus types 1 and 2, and 14 enteroviruses in chronic fatigue syndrome: is there evidence of activation of a nonspecific polyclonal immune response?
20 CFS, 20 controls
Coxsackievirus B1, B4 antibody titer
Comparison of Coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients
Nairn et al.
100 patients, 100 controls
PCR, antibody in neutralisation assay
Yes for PCR, not for NA
Detection of enterovirus—specific RNA in serum: the relationship to chronic fatigue
Clements et al.
88 patients, 126 controls
Serum, buffy coat, stool
Phylogenetic analysis of short enteroviral sequences from patients with chronic fatigue syndrome
238 CFS, 130 controls
Serum, throat swaps
Detection of enterovirus in human skeletal muscle from patients with chronic inflammatory muscle disease or fibromyalgia and healthy subjects
Douche-Aourik et al.
30 CFS/Fibromyalgia patients, 29 controls
Enterovirus related metabolic myopathy: a postviral fatigue syndrome.
Lane et al.
48 CFS, 29 controls
Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach
Chia et al.
165 CFS,34 controls
VP-1 staining, RT-PCR
Acute enterovirus infection followed by myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and viral persistence
Chia et al.
Gastric biopsies, blood
VP-1 staining, RT-PCR
Chronic fatigue syndrome: clinical condition associated with immune activation
Landay et al.
63 CFS, 40 controls
Coxsackievirus B4 antibodies
Prevalence yes, titer not
Studies on enterovirus in patients with chronic fatigue syndrome
Gow et al.
131 CFS, 101 controls (neuromuscular disorders)
No findings of enteroviruses in Swedish patients with chronic fatigue syndrome
Lindh et al.
Investigation by polymerase chain reaction of enteroviral infection in patients with chronic fatigue syndrome
Enteroviruses and the chronic fatigue syndrome
76 CFS, 76 controls
Viral serologies in patients with chronic fatigue and chronic fatigue syndrome
508 CFS, 30 controls
Coxsackievirus B antibodies
Gow et al. reported on the detection of enteroviral RNA in muscle biopsies from 53% of 60 ME/CFS in comparison to 15% of 41 controls . Furthermore, quadriceps muscle biopsy samples from 20.8% of the 48 ME/CFS patients were found to be positive for enterovirus sequences by reverse transcription (RT)-PCR, while all 29 control samples were negative . In a study by Bowles et al. , molecular hybridization detected enteroviral RNA in muscle biopsies from 41 of 148 patients with ME/CFS, 25 of 96 patients with inflammatory muscle disease, and only two of 152 controls. In an earlier study, the same group had postulated that the enteroviral persistence in the muscle might be caused by a defect in the control of viral RNA synthesis as they found approximately equal amounts of enteroviral positive and negative RNA strands, in contrast to lytic infections, in which positive RNA strands dominate . They speculated that persistence of viral RNA without synthesis of viruses could contribute to muscle dysfunction. In 2003, detection of enteroviral RNA without production of viral proteins was reported by Douche-Aourik et al., whose analysis of muscle biopsy samples revealed virus RNA positive samples in 13% (4/30) of ME/CFS patients and none of the controls . Enteroviral VP-1 protein could not be stained by immunohistochemistry in any of the samples.
In 2008, Chia et al. found that 135/165 (82%) antrum biopsy specimens stained positive for enterovirus VP1 within parietal cells, whereas significantly fewer controls were stained positive (7/34, 20%) . Enterovirus RNA was detected in 9/24 (37%) paraffin embedded biopsy samples, and only 1/21 controls had detectable enterovirus RNA. One out of 3 patients had detectable enterovirus RNA from two follow-up samples taken 4 years apart, whereas 5 patient samples showed transient growth of non-cytopathic enteroviruses . In another study from the same group, 3 patients with acute enteroviral infection developed symptoms of ME/CFS during follow-up. Enteroviral persistence was demonstrated by detection of enteroviral RNA sequences in gastric biopsy specimens and in peripheral blood leukocytes (PBL) by qualitative RT-PCR . It was also shown by Galbraith et al. that enteroviruses, 19/20 of which were substantially different from previously described enteroviruses, can establish persistent infection, and in some cases, they can lead to the manifestation of ME/CFS . In the group of patients who had been referred for assessment of fatigue, 44/238 serum samples and 29/175 throat swab samples were positive by enteroviral PCR assay, while sera from 3/130 healthy individuals were positive using the enteroviral PCR assay . In a following study, eight individuals with ME/CFS were positive for enteroviral sequences, which were detected by PCR in two serum samples taken at least 5 months apart . In addition, serological evidence has indicated that enteroviral activity may contribute to ME/CFS; increased titers of antibodies against coxsackieviruses B1 and B4 have been found among patients , and in a separate group, enterovirus IgG class antibodies were present in 49% of ME/CFS patients. Within this cohort, acute infections were observed in 5% of patients . The results of antiviral treatment provided additional arguments in support of a potential role for enteroviruses in the pathogenesis of ME/CFS, as 7 out of 10 ME/CFS patients with persistent enterovirus infection were successfully treated with alpha interferon and ribavirin or a combination of alpha and gamma interferon .
A study focussing on the analysis of immune activation in ME/CFS found a significantly higher prevalence of coxsackievirus infection in 63 ME/CFS patients (90%) in comparison to 40 controls (65%). However, geometric mean antibody IgG titers were similar in both groups . In contrast, another study found elevated IgG-titers against coxsackievirus in only 6% of 107 ME/CFS patients, arguing against a major role of active coxsackievirus infection in ME/CFS, at least in that cohort.
Other studies were not able to detect enterovirus infection in ME/CFS patients’ blood, stool, serum, cerebrospinal fluid (CSF) and muscle biopsy samples [76, 81, 103–105]. In addition, there were no significant differences in the rates of detection of enteroviral RNA in muscle biopsies from a group of patients with ME/CFS (26.4%), compared with a group of patients with other neuromuscular disorders (19.8%). It was concluded that persistent enterovirus infection is unlikely to play a pathogenic role in ME/CFS, although an effect in initiating the disease process cannot be excluded .
B19V is an immunomodulating single-stranded DNA virus belonging to the Parvoviridae family, the Parvovirinae subfamily, and the Erythrovirus genus. It was discovered in 1975 in the serum of an apparently healthy donor .
B19V was first associated with a human disease in 1981 . It is frequently detected in children, and consequently, 60–80% of adults have antibodies against this virus. It can cause rash, Erythema infectiosum or the fifth disease, arthralgia, various skin lesions, neutropenia, liver and lung disorders, papular-purpuric gloves and socks syndrome, hepato-biliary diseases, cardiac syndromes, autoimmune and neurological diseases, transient aplastic crisis with a short life-span and aplasia of red blood cells that is observed in immunocompromised patients [109, 110]. Viral DNA is eliminated from the serum within 4–5 months, and antibodies rapidly decrease. Many years after the primary infection and acute phase, B19V can persist in an organism, and persistent B19V infection has been investigated as a possible etiological agent in cases of encephalitis, encephalopathy, arthritis, autoimmune processes, fatigue and ME/CFS [111, 112].
Initial studies using PCR to examine the presence of B19V DNA in serum and bone marrow aspirates did not find evidence of involvement of B19V infection in bone marrow dysfunction in any of seven ME/CFS patients. Out of these 7 patients, only 1 patient had B19V specific antibodies . Additionally, an analysis of 22 monozygotic twins revealed the presence of B19V genomic sequences in only one of the healthy twins as detected by PCR .
A link between B19V infection and subsequent onset of ME/CFS (1–3 years post-infection) has been published . The results from this analysis revealed a significant association between the development of ME/CFS and high stress levels, as determined through the use of questionnaires, during acute B19V infection. Later, B19V DNA was found in plasma samples from 3/58 ME/CFS patients and 2/49 healthy controls, while IgG class antibodies were observed in 52% and 57% of patients and controls, respectively, and IgM class antibodies not present at all . Due to the detection of B19V DNA in gastro-intestinal biopsies from 40% of patients and fewer than 15% of controls, some researchers have concluded that, at least in a subset of patients, B19V could be involved in the pathogenesis of ME/CFS .
While analysing the presence of B19V infection markers in the serum of 200 ME/CFS patients and 200 healthy blood donors using real-time PCR, B19V DNA was detected in 11 patients with ME/CFS but in none of the healthy blood donors. A significant difference was not revealed in B19V seroprevalence (the proportion of individuals with anti-B19 VP2 IgG class antibodies) between patients with ME/CFS, 75% of whom were seropositive, and donors, who had a total seroprevalence of 78%. Meanwhile, anti-B19V VP2 IgM class antibodies were found in 4 patients. In addition, 41.5% of patients and only 7% of donors had IgG class antibodies against non-structural (NS1) protein, whereas B19V specific NS1 IgM class antibodies were found in 3 patients and one donor. The presence of B19V specific NS1 antibodies indicates a severe and persistent or chronic B19V infection; in this study, 73% of those with anti-NS1 antibodies suffered from joint pain, and positivity for these antibodies in ME/CFS patients was associated with greater expression of the human ME/CFS-associated genes NHLH1 and GABPA . Another report described finding anti-VP2 IgG class antibodies in 74% of the analysed patients with ME/CFS and IgM in 1 patient. As was the case in the aforementioned study by Kerr et al., B19V seroprevalence among ME/CFS patients was shown to be similar to the percentage in the general population . More recently, B19V VP2 specific antibodies were detected in plasma samples from 85% of the ME/CFS patients and 61% of practically healthy individuals . Moreover, active B19V infection was detected in 28% of ME/CFS patients compared to 2% of controls using nested PCR, and active infection was linked to an increased frequency of joint pain . In spite of these studies, there is no consensus on B19V as a causative agent of ME/CFS.
Xenotropic murine leukemia related virus (XMRV) belongs to the Retroviridae family, Orthoretrovirinae subfamily and Gammaretrovirus genus, which was identified in 2006 while studying the lack of ribonuclease L coding antiviral gene RNASEL function in patients with prostate cancer . The genome has 95% homology with several endogenous murine retroviruses and 94% homology with exogenous murine retroviruses . However, Paprotka et al. concluded that XMRV is probably a recombinant virus, which was generated by the recombination of two murine retroviruses (pre-XMRV1 and pre-XMRV-2) during passaging of prostate cancer cell lines in nude mice within a time period ranging from 1993 to 1996 .
XMRV was discovered in patients with prostate cancer, and publications reported potential associations between the virus and other diseases. The observations of RNase L proteolysis in PBMC from patients with ME/CFS and infectious-like chronic immune system activation led to examination of XMRV in these patients [119, 120]. The XMRV gag gene sequence was detected by nested PCR in PBMCs of 67% out of 100 patients PBMCs but only in 3.7% out of 218 healthy donors PBMCs, and further analysis revealed 99% sequence identity with XMRV by sequencing viral genomes from 3 patients . However, Science retracted this article in 2011, citing poor quality control in the experiments, the omission of important information regarding treatment of the ME/CFS-patient PBMCs, and scepticism of the validity of the study .
In 2010, Lo et al. reported on the detection of MLV-related virus gag gene sequences in 86.5% out of 37 patients and 6.8% out of 44 control group individuals . However, in 2012, the authors retracted the publication. Later, many researchers published their efforts to detect XMRV in patients with ME/CFS and donors using serological and molecular methods. No evidence linking XMRV to ME/CFS was found in studies carried out in Germany, China, Sweden, the United Kingdom, Japan, the United States of America, Canada, the Netherlands, Latvia and Italy [123–135]. The presence of XMRV or MLV-related sequences, antibodies, or infectious virus was not confirmed in large ME/CFS patient groups, including a subset of the patients previously reported to be XMRV-positive by Lombardi and colleagues .
It has been suggested that the earlier positive findings were based on laboratory contamination [136–140]. Studies have shown that commercial reagents and clinical samples could be contaminated with MLV-related virus genomic sequences containing murine DNA, and cloned or amplified XMRV DNA might be the source of contamination. It could also originate from frequently used XMRV-infected prostate cancer cell line 22Rv1 . Various geographic localizations may explain differences in some results, but not in the same country. Another reason for problems with XMRV detection was thought to be XMRV sequence variation or the presence of XMRV-like viruses. XMRV strain identity is 99%; therefore, the existence of distinct or related viruses is possible, and detection of them with PCR or some other methods can be difficult . After several years of studies, large effort and expenses from clinicians, scientists and patients, it was concluded that there is no association between XMRV and human diseases, and positive results were consequences of contamination .
Studies on several other retroviruses (HTLV-I and -II, HIV-1/2, spuma viruses) in ME/CFS were performed. Whereas DeFreitas reported on the presence of antibodies to HTLV-II and retroviral sequences in blood cells in patients with ME/CFS, these findings could not be reproduced by other groups [76, 143, 144]. Therefore, the theory of retroviral etiology in ME/CFS is not currently supported.
Another post-viral fatigue-causing virus is a single-stranded positive-sense RNA virus—Ross River virus (RRV), which belongs to the family Togaviridae, genus Alphavirus. Mosquitoes transmit this viral infection from infected animals to humans, and symptoms of the infection overlap with the symptoms of ME/CFS. Back in 1996, Selden and Cameron published a study in which such symptoms as joint pain, persistent tiredness, lethargy, myalgia, lymphadenopathy, headache, and depression were observed even 30 months after infection with RRV in South Australia .
Using an antibody-dependent enhancement mechanism, RRV has been found to infect macrophages and enable suppression of specific antiviral genes expressed by these cells, which results in unimpeded replication . An additional study by these two authors showed suppression of functional activity of STAT1 and NF-κB transcription factor protein complexes due to antibody-dependent enhancement of RRV infection .
Later, acute RRV or EBV infection followed by fever, malaise, pain, fatigue, and mood and concentration disorders were correlated with elevated levels of pro-inflammatory cytokines . Analysing the same patient cohort in Australia, Hickie and colleagues studied the prevalence and course of post-infectious fatigue and chronic fatigue following acute RRV, EBV and Coxiella burnetii infection, demonstrating that severity of acute viral infection and the host response to it may determine the course of post-infectious syndrome and ME/CFS . More recent attempts to find a possible illness-specific signature of peripheral blood gene expression in patients with post-infectious fatigue caused by RRV, EBV, or Coxiella burnetii, was not successful . Subsequently, this team hypothesized that inflammatory cytokines influence the CNS, resulting in neurocognitive disturbances following acute infection, and therefore, certain infectious agent may not determine symptoms. Moreover, genetic predisposition of specific cytokine expression has been found to affect cognitive manifestations, particularly during acute infection .
Currently available data on the role of chronic viral infection with ME/CFS is still controversial, showing potential viral involvement for at least a subgroup of ME/CFS patients. Therefore, it is necessary to assess the presence and markers of viral activity at the initial stage of the disease to evaluate possible etiological factors and conduct longitudinal studies in order to assess active viral infection and symptom severity variations over time. Moreover, results should be compared not only between ME/CFS patients and controls, but also with other co-morbidities to assess specificity of suggested biomarkers.
Considering ME/CFS heterogeneity, the use of clinical characteristics and biomarkers to enable definition of the disease subtypes is crucial. In addition, longitudinal and standardized studies determining ME/CFS course and therapy effectiveness with follow-up measurements in dynamics should be accomplished. This will allow prognosis of the disease development and promote development of a specific definition for diagnostics and a treatment plan.
Use of quantitative assays rather than qualitative assays to assess the extent of the viral load instead of simple detection of presence or absence. This may facilitate monitoring of a response to treatment; however, diurnal variations and individual response on treatment should be taken into account. Further comprehensive serological testing may help to identify a signature of active infection.
Use of additional biological samples together with blood and serum will be useful in determining the localization and distribution of biomarkers, as well as pathogenicity. Using hair follicles, virus integration can be detected. Similarly throat swab and stool samples can be used for detection of enteroviruses.
Functional studies to compliment clinical biomarker studies in order to clarify functions and interactions of genes, transcripts, proteins, and immune cells and molecules in cases of ME/CFS. This will facilitate understanding of the disease aetiology as well as development and maintenance pathways, and thereby, potential prevention and treatment strategies. However, this strategy requires definition of ME/CFS subgroups.
Use of high throughput methods to gain broader insight into potential biomarkers for infections by obtaining and analysing large-scale data, which will raise the quality and significance of the research.
Confirmation of results by validation studies and multi-centre cohort studies to obtain generalizability of the study and promote implementation of credible biomarkers usable worldwide.
BKP, SR, NH conceived the idea and wrote the first draft of the manuscript; ZN, EE, ES, TH, CS, MM contributed towards writing and final editing of the manuscript. All authors read and approved the final manuscript.
We thank EUROMENE, a part of COST Action CA15111 under EU Framework Program Horizon 2020 for supporting the work.
The authors declare that they have no competing interests.
Availability of data and materials
Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.
Consent for publication
Ethics approval and consent to participate
This review is based upon work from European Network on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (EUROMENE) as part of COST Action CA15111 supported by the EU Framework Program Horizon 2020 (Website: http://www.cost.eu/COST_Actions/ca/CA15111). Other funding sources—the Bulgarian National Science Fund [ДКOCT 01/9 to E.S.], Solve ME/CFS Initiative, USA (to BKP).
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- Brurberg KG, Fonhus MS, Larun L, Flottorp S, Malterud K. Case definitions for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME): a systematic review. BMJ Open. 2014;4:e003973.PubMedPubMed CentralView ArticleGoogle Scholar
- Underhill RA. Myalgic encephalomyelitis, chronic fatigue syndrome: an infectious disease. Med Hypotheses. 2015;85:765–73.PubMedView ArticlePubMed CentralGoogle Scholar
- Carruthers M, Kumar Jain A, De Meirleir K, Peterson DL, Klimas NG. Myalgic encephalomyelitis/chronic fatigue syndrome: clinical working case definition, diagnostic and treatment protocols. J Chronic Fatigue Syndr. 2003;11:7–115.View ArticleGoogle Scholar
- Bested AC, Marshall LM. Review of myalgic encephalomyelitis/chronic fatigue syndrome: an evidence-based approach to diagnosis and management by clinicians. Rev Environ Health. 2015;30:223–49.PubMedView ArticlePubMed CentralGoogle Scholar
- Lorusso L, Mikhaylova SV, Capelli E, Ferrari D, Ngonga GK, Ricevuti G. Immunological aspects of chronic fatigue syndrome. Autoimmun Rev. 2009;8:287–91.PubMedView ArticlePubMed CentralGoogle Scholar
- Jason LA, Richman JA, Rademaker AW, Jordan KM, Plioplys AV, Taylor RR, McCready W, Huang CF, Plioplys S. A community-based study of chronic fatigue syndrome. Arch Intern Med. 1999;159:2129–37.PubMedView ArticlePubMed CentralGoogle Scholar
- Bansal AS, Bradley AS, Bishop KN, Kiani-Alikhan S, Ford B. Chronic fatigue syndrome, the immune system and viral infection. Brain Behav Immun. 2012;26:24–31.PubMedView ArticlePubMed CentralGoogle Scholar
- Johnston S, Brenu EW, Staines D, Marshall-Gradisnik S. The prevalence of chronic fatigue syndrome/myalgic encephalomyelitis: a meta-analysis. Clin Epidemiol. 2013;5:105–10.PubMedPubMed CentralView ArticleGoogle Scholar
- Steele L, Dobbins JG, Fukuda K, Reyes M, Randall B, Koppelman M, Reeves WC. The epidemiology of chronic fatigue in San Francisco. Am J Med. 1998;105:83S–90S.PubMedView ArticlePubMed CentralGoogle Scholar
- Silverman RH, Nguyen C, Weight CJ, Klein EA. The human retrovirus XMRV in prostate cancer and chronic fatigue syndrome. Nat Rev Urol. 2010;7:392–402.PubMedView ArticleGoogle Scholar
- Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med. 1994;121:953–9.PubMedView ArticleGoogle Scholar
- Carruthers BM, van de Sande MI, De Meirleir KL, Klimas NG, Broderick G, Mitchell T, Staines D, Powles AC, Speight N, Vallings R, et al. Myalgic encephalomyelitis: international consensus criteria. J Intern Med. 2011;270:327–38.PubMedPubMed CentralView ArticleGoogle Scholar
- Afari N, Buchwald D. Chronic fatigue syndrome: a review. Am J Psychiatry. 2003;160:221–36.PubMedView ArticleGoogle Scholar
- Prins JB, van der Meer JW, Bleijenberg G. Chronic fatigue syndrome. Lancet. 2006;367:346–55.PubMedView ArticleGoogle Scholar
- Krueger GR, Ablashi D. Human herpesvirus-6, second edition, general virology, epidemiology and clinical pathology. Perspectives in medical virology. Netherlands: Elseviere; 2006. p. 251–62.Google Scholar
- Fluge O, Bruland O, Risa K, Storstein A, Kristoffersen EK, Sapkota D, Naess H, Dahl O, Nyland H, Mella O. Benefit from B-lymphocyte depletion using the anti-CD20 antibody rituximab in chronic fatigue syndrome. A double-blind and placebo-controlled study. PLoS ONE. 2011;6:e26358.PubMedPubMed CentralView ArticleGoogle Scholar
- Straus SE, Tosato G, Armstrong G, Lawley T, Preble OT, Henle W, Davey R, Pearson G, Epstein J, Brus I, et al. Persisting illness and fatigue in adults with evidence of Epstein–Barr virus infection. Ann Intern Med. 1985;102:7–16.PubMedView ArticleGoogle Scholar
- Holmes GP, Kaplan JE, Stewart JA, Hunt B, Pinsky PF, Schonberger LB. A cluster of patients with a chronic mononucleosis-like syndrome. Is Epstein–Barr virus the cause? JAMA. 1987;257:2297–302.PubMedView ArticleGoogle Scholar
- Martin WJ. Detection of RNA sequences in cultures of a stealth virus isolated from the cerebrospinal fluid of a health care worker with chronic fatigue syndrome. Case report. Pathobiology. 1997;65:57–60.PubMedView ArticleGoogle Scholar
- Buchwald D, Cheney PR, Peterson DL, Henry B, Wormsley SB, Geiger A, Ablashi DV, Salahuddin SZ, Saxinger C, Biddle R, et al. A chronic illness characterized by fatigue, neurologic and immunologic disorders, and active human herpesvirus type 6 infection. Ann Intern Med. 1992;116:103–13.PubMedView ArticlePubMed CentralGoogle Scholar
- Yalcin S, Kuratsune H, Yamaguchi K, Kitani T, Yamanishi K. Prevalence of human herpesvirus 6 variants A and B in patients with chronic fatigue syndrome. Microbiol Immunol. 1994;38:587–90.PubMedView ArticleGoogle Scholar
- Ablashi DV, Eastman HB, Owen CB, Roman MM, Friedman J, Zabriskie JB, Peterson DL, Pearson GR, Whitman JE. Frequent HHV-6 reactivation in multiple sclerosis (MS) and chronic fatigue syndrome (CFS) patients. J Clin Virol. 2000;16:179–91.PubMedView ArticleGoogle Scholar
- McGarry F, Gow J, Behan PO. Enterovirus in the chronic fatigue syndrome. Ann Intern Med. 1994;120:972–3.PubMedView ArticleGoogle Scholar
- Holmes MJ, Diack DS, Easingwood RA, Cross JP, Carlisle B. Electron microscopic immunocytological profiles in chronic fatigue syndrome. J Psychiatr Res. 1997;31:115–22.PubMedView ArticleGoogle Scholar
- Nasralla M, Haier J, Nicolson GL. Multiple mycoplasmal infections detected in blood of patients with chronic fatigue syndrome and/or fibromyalgia syndrome. Eur J Clin Microbiol Infect Dis. 1999;18:859–65.PubMedView ArticleGoogle Scholar
- Komaroff AL. Is human herpesvirus-6 a trigger for chronic fatigue syndrome? J Clin Virol. 2006;37(Suppl 1):S39–46.PubMedView ArticleGoogle Scholar
- Morinet F, Corruble E. Chronic fatigue syndrome and viral infections. In: Snell CR, editor. An international perspective on the future of research in chronic fatigue syndrome. Croatia: InTech; 2012. p. 1–12.Google Scholar
- De Bolle L, Van Loon J, De Clercq E, Naesens L. Quantitative analysis of human herpesvirus 6 cell tropism. J Med Virol. 2005;75:76–85.PubMedView ArticleGoogle Scholar
- Sotzny F, Blanco J, Capelli E, Castro-Marrero J, Steiner S, Murovska M, Scheibenbogen C, European Network on MC. Myalgic encephalomyelitis/chronic fatigue syndrome—evidence for an autoimmune disease. Autoimmun Rev. 2018;17:601–9.PubMedView ArticleGoogle Scholar
- Roizman B, Carmichael LE, Deinhardt F, de The G, Nahmias AJ, Plowright W, Rapp F, Sheldrick P, Takahashi M, Wolf K. Herpesviridae. Definition, provisional nomenclature, and taxonomy. The Herpesvirus Study Group, the International Committee on Taxonomy of Viruses. Intervirology. 1981;16:201–17.PubMedView ArticlePubMed CentralGoogle Scholar
- Salahuddin SZ, Ablashi DV, Markham PD, Josephs SF, Sturzenegger S, Kaplan M, Halligan G, Biberfeld P, Wong-Staal F, Kramarsky B, et al. Isolation of a new virus, HBLV, in patients with lymphoproliferative disorders. Science. 1986;234:596–601.PubMedView ArticlePubMed CentralGoogle Scholar
- Frenkel N, Schirmer EC, Wyatt LS, Katsafanas G, Roffman E, Danovich RM, June CH. Isolation of a new herpesvirus from human CD4+ T cells. Proc Natl Acad Sci USA. 1990;87:748–52.PubMedView ArticlePubMed CentralGoogle Scholar
- Yamanishi K, Okuno T, Shiraki K, Takahashi M, Kondo T, Asano Y, Kurata T. Identification of human herpesvirus-6 as a causal agent for exanthem subitum. Lancet. 1988;1:1065–7.PubMedView ArticlePubMed CentralGoogle Scholar
- Kondo K, Hayakawa Y, Mori H, Sato S, Kondo T, Takahashi K, Minamishima Y, Takahashi M, Yamanishi K. Detection by polymerase chain reaction amplification of human herpesvirus 6 DNA in peripheral blood of patients with exanthem subitum. J Clin Microbiol. 1990;28:970–4.PubMedPubMed CentralGoogle Scholar
- Caselli E, Di Luca D. Molecular biology and clinical associations of Roseoloviruses human herpesvirus 6 and human herpesvirus 7. New Microbiol. 2007;30:173–87.PubMedPubMed CentralGoogle Scholar
- Bassig BA, Willhauck-Fleckenstein M, Shu XO, Koh WP, Gao YT, Purdue MP, Xiang YB, Adams-Haduch J, Wang R, Brenner N, et al. Serologic markers of viral infection and risk of non-Hodgkin lymphoma: a pooled study of three prospective cohorts in China and Singapore. Int J Cancer. 2018;143:570–9.PubMedView ArticlePubMed CentralGoogle Scholar
- Kaufer BB, Flamand L. Chromosomally integrated HHV-6: impact on virus, cell and organismal biology. Curr Opin Virol. 2014;9C:111–8.View ArticleGoogle Scholar
- Prusty BK, Krohne G, Rudel T. Reactivation of chromosomally integrated human herpesvirus-6 by telomeric circle formation. PLoS Genet. 2013;9:e1004033.PubMedPubMed CentralView ArticleGoogle Scholar
- Prusty BK, Gulve N, Rasa S, Murovska M, Hernandez PC, Ablashi DV. Possible chromosomal and germline integration of human herpesvirus 7. J Gen Virol. 2017;98:266–74.PubMedView ArticlePubMed CentralGoogle Scholar
- Dockrell DH. Human herpesvirus 6: molecular biology and clinical features. J Med Microbiol. 2003;52:5–18.PubMedView ArticleGoogle Scholar
- Mirandola P, Sponzilli I, Solenghi E, Micheloni C, Rinaldi L, Gobbi G, Vitale M. Down-regulation of human leukocyte antigen class I and II and beta 2-microglobulin expression in human herpesvirus-7-infected cells. J Infect Dis. 2006;193:917–26.PubMedView ArticlePubMed CentralGoogle Scholar
- Dagna L, Pritchett JC, Lusso P. Immunomodulation and immunosuppression by human herpesvirus 6A and 6B. Future Virol. 2013;8:273–87.PubMedPubMed CentralView ArticleGoogle Scholar
- Katsafanas GC, Schirmer EC, Wyatt LS, Frenkel N. In vitro activation of human herpesviruses 6 and 7 from latency. Proc Natl Acad Sci USA. 1996;93:9788–92.PubMedView ArticleGoogle Scholar
- Boutolleau D, Fernandez C, Andre E, Imbert-Marcille BM, Milpied N, Agut H, Gautheret-Dejean A. Human herpesvirus (HHV)-6 and HHV-7: two closely related viruses with different infection profiles in stem cell transplantation recipients. J Infect Dis. 2003;187:179–86.PubMedView ArticleGoogle Scholar
- Hall CB, Caserta MT, Schnabel KC, McDermott MP, Lofthus GK, Carnahan JA, Gilbert LM, Dewhurst S. Characteristics and acquisition of human herpesvirus (HHV) 7 infections in relation to infection with HHV-6. J Infect Dis. 2006;193:1063–9.PubMedView ArticleGoogle Scholar
- Chapenko S, Millers A, Nora Z, Logina I, Kukaine R, Murovska M. Correlation between HHV-6 reactivation and multiple sclerosis disease activity. J Med Virol. 2003;69:111–7.PubMedView ArticlePubMed CentralGoogle Scholar
- Seeley WW, Marty FM, Holmes TM, Upchurch K, Soiffer RJ, Antin JH, Baden LR, Bromfield EB. Post-transplant acute limbic encephalitis: clinical features and relationship to HHV6. Neurology. 2007;69:156–65.PubMedView ArticlePubMed CentralGoogle Scholar
- Arbuckle JH, Medveczky MM, Luka J, Hadley SH, Luegmayr A, Ablashi D, Lund TC, Tolar J, De Meirleir K, Montoya JG, et al. The latent human herpesvirus-6A genome specifically integrates in telomeres of human chromosomes in vivo and in vitro. Proc Natl Acad Sci USA. 2010;107:5563–8.PubMedView ArticlePubMed CentralGoogle Scholar
- Mardivirin L, Descamps V, Lacroix A, Delebassee S, Ranger-Rogez S. Early effects of drugs responsible for DRESS on HHV-6 replication in vitro. J Clin Virol. 2009;46:300–2.PubMedView ArticlePubMed CentralGoogle Scholar
- Mardivirin L, Valeyrie-Allanore L, Branlant-Redon E, Beneton N, Jidar K, Barbaud A, Crickx B, Ranger-Rogez S, Descamps V. Amoxicillin-induced flare in patients with DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms): report of seven cases and demonstration of a direct effect of amoxicillin on Human Herpesvirus 6 replication in vitro. Eur J Dermatol. 2010;20:68–73.PubMedGoogle Scholar
- Martinez A, Alvarez-Lafuente R, Mas A, Bartolome M, Garcia-Montojo M, de Las Heras V, de la Concha EG, Arroyo R, Urcelay E. Environment–gene interaction in multiple sclerosis: human herpesvirus 6 and MHC2TA. Hum Immunol. 2007;68:685–9.PubMedView ArticleGoogle Scholar
- Lusso P, Crowley RW, Malnati MS, Di Serio C, Ponzoni M, Biancotto A, Markham PD, Gallo RC. Human herpesvirus 6A accelerates AIDS progression in macaques. Proc Natl Acad Sci USA. 2007;104:5067–72.PubMedView ArticlePubMed CentralGoogle Scholar
- Gorniak RJ, Young GS, Wiese DE, Marty FM, Schwartz RB. MR imaging of human herpesvirus-6-associated encephalitis in 4 patients with anterograde amnesia after allogeneic hematopoietic stem-cell transplantation. AJNR Am J Neuroradiol. 2006;27:887–91.PubMedPubMed CentralGoogle Scholar
- Chevret L, Boutolleau D, Halimi-Idri N, Branchereau S, Baujard C, Fabre M, Gautheret-Dejean A, Debray D. Human herpesvirus-6 infection: a prospective study evaluating HHV-6 DNA levels in liver from children with acute liver failure. J Med Virol. 2008;80:1051–7.PubMedView ArticlePubMed CentralGoogle Scholar
- Ablashi DV, Salahuddin SZ, Josephs SF, Balachandran N, Krueger GR, Gallo RC. Human herpesvirus-6 (HHV-6) (short review). In Vivo. 1991;5:193–9.PubMedPubMed CentralGoogle Scholar
- Komaroff AL. Chronic fatigue syndromes: relationship to chronic viral infections. J Virol Methods. 1988;21:3–10.PubMedView ArticlePubMed CentralGoogle Scholar
- Ablashi DV. Viral studies of chronic fatigue syndrome. Clin Infect Dis. 1994;18(Suppl 1):S130–3.PubMedView ArticlePubMed CentralGoogle Scholar
- Josephs SF, Henry B, Balachandran N, Strayer D, Peterson D, Komaroff AL, Ablashi DV. HHV-6 reactivation in chronic fatigue syndrome. Lancet. 1991;337:1346–7.PubMedView ArticlePubMed CentralGoogle Scholar
- Patnaik M, Komaroff AL, Conley E, Ojo-Amaize EA, Peter JB. Prevalence of IgM antibodies to human herpesvirus 6 early antigen (p41/38) in patients with chronic fatigue syndrome. J Infect Dis. 1995;172:1364–7.PubMedView ArticleGoogle Scholar
- Secchiero P, Carrigan DR, Asano Y, Benedetti L, Crowley RW, Komaroff AL, Gallo RC, Lusso P. Detection of human herpesvirus 6 in plasma of children with primary infection and immunosuppressed patients by polymerase chain reaction. J Infect Dis. 1995;171:273–80.PubMedView ArticleGoogle Scholar
- Koelle DM, Barcy S, Huang ML, Ashley RL, Corey L, Zeh J, Ashton S, Buchwald D. Markers of viral infection in monozygotic twins discordant for chronic fatigue syndrome. Clin Infect Dis. 2002;35:518–25.PubMedView ArticleGoogle Scholar
- Chapenko S, Krumina A, Logina I, Rasa S, Chistjakovs M, Sultanova A, Viksna L, Murovska M. Association of active human herpesvirus-6, -7 and parvovirus b19 infection with clinical outcomes in patients with myalgic encephalomyelitis/chronic fatigue syndrome. Adv Virol. 2012;2012:205085.PubMedPubMed CentralView ArticleGoogle Scholar
- Sairenji T, Yamanishi K, Tachibana Y, Bertoni G, Kurata T. Antibody responses to Epstein–Barr virus, human herpesvirus 6 and human herpesvirus 7 in patients with chronic fatigue syndrome. Intervirology. 1995;38:269–73.PubMedView ArticleGoogle Scholar
- Chapenko S, Krumina A, Kozireva S, Nora Z, Sultanova A, Viksna L, Murovska M. Activation of human herpesviruses 6 and 7 in patients with chronic fatigue syndrome. J Clin Virol. 2006;37(Suppl 1):S47–51.PubMedView ArticleGoogle Scholar
- Di Luca D, Zorzenon M, Mirandola P, Colle R, Botta GA, Cassai E. Human herpesvirus 6 and human herpesvirus 7 in chronic fatigue syndrome. J Clin Microbiol. 1995;33:1660–1.PubMedPubMed CentralGoogle Scholar
- Wallace HL 2nd, Natelson B, Gause W, Hay J. Human herpesviruses in chronic fatigue syndrome. Clin Diagn Lab Immunol. 1999;6:216–23.PubMedPubMed CentralGoogle Scholar
- Reeves WC, Stamey FR, Black JB, Mawle AC, Stewart JA, Pellett PE. Human herpesviruses 6 and 7 in chronic fatigue syndrome: a case–control study. Clin Infect Dis. 2000;31:48–52.PubMedView ArticleGoogle Scholar
- Fremont M, Metzger K, Rady H, Hulstaert J, De Meirleir K. Detection of herpesviruses and parvovirus B19 in gastric and intestinal mucosa of chronic fatigue syndrome patients. In Vivo. 2009;23:209–13.PubMedGoogle Scholar
- Oakes B, Hoagland-Henefield M, Komaroff AL, Erickson JL, Huber BT. Human endogenous retrovirus-K18 superantigen expression and human herpesvirus-6 and human herpesvirus-7 viral loads in chronic fatigue patients. Clin Infect Dis. 2013;56:1394–400.PubMedView ArticleGoogle Scholar
- Aoki R, Kobayashi N, Suzuki G, Kuratsune H, Shimada K, Oka N, Takahashi M, Yamadera W, Iwashita M, Tokuno S, et al. Human herpesvirus 6 and 7 are biomarkers for fatigue, which distinguish between physiological fatigue and pathological fatigue. Biochem Biophys Res Commun. 2016;478:424–30.PubMedView ArticlePubMed CentralGoogle Scholar
- Lerner AM, Beqaj SH, Deeter RG, Fitzgerald JT. IgM serum antibodies to Epstein–Barr virus are uniquely present in a subset of patients with the chronic fatigue syndrome. In Vivo. 2004;18:101–6.PubMedPubMed CentralGoogle Scholar
- Loebel M, Strohschein K, Giannini C, Koelsch U, Bauer S, Doebis C, Thomas S, Unterwalder N, von Baehr V, Reinke P, et al. Deficient EBV-specific B- and T-cell response in patients with chronic fatigue syndrome. PLoS ONE. 2014;9:e85387.PubMedPubMed CentralView ArticleGoogle Scholar
- Loebel M, Eckey M, Sotzny F, Hahn E, Bauer S, Grabowski P, Zerweck J, Holenya P, Hanitsch LG, Wittke K, et al. Serological profiling of the EBV immune response in Chronic Fatigue Syndrome using a peptide microarray. PLoS ONE. 2017;12:e0179124.PubMedPubMed CentralView ArticleGoogle Scholar
- Manian FA. Simultaneous measurement of antibodies to Epstein–Barr virus, human herpesvirus 6, herpes simplex virus types 1 and 2, and 14 enteroviruses in chronic fatigue syndrome: is there evidence of activation of a nonspecific polyclonal immune response? Clin Infect Dis. 1994;19:448–53.PubMedView ArticleGoogle Scholar
- Levine PH, Jacobson S, Pocinki AG, Cheney P, Peterson D, Connelly RR, Weil R, Robinson SM, Ablashi DV, Salahuddin SZ, et al. Clinical, epidemiologic, and virologic studies in four clusters of the chronic fatigue syndrome. Arch Intern Med. 1992;152:1611–6.PubMedView ArticleGoogle Scholar
- Landay AL, Jessop C, Lennette ET, Levy JA. Chronic fatigue syndrome: clinical condition associated with immune activation. Lancet. 1991;338:707–12.PubMedView ArticleGoogle Scholar
- Gupta S, Vayuvegula B. A comprehensive immunological analysis in chronic fatigue syndrome. Scand J Immunol. 1991;33:319–27.PubMedView ArticleGoogle Scholar
- Zorzenon M, Rukh G, Botta GA, Colle R, Barsanti LA, Ceccherini-Nelli L. Active HHV-6 infection in chronic fatigue syndrome patients from Italy: new data. J Chronic Fatigue Syndr. 1996;2:3–12.View ArticleGoogle Scholar
- Buchwald D, Ashley RL, Pearlman T, Kith P, Komaroff AL. Viral serologies in patients with chronic fatigue and chronic fatigue syndrome. J Med Virol. 1996;50:25–30.PubMedView ArticleGoogle Scholar
- Zhang L, Gough J, Christmas D, Mattey DL, Richards SC, Main J, Enlander D, Honeybourne D, Ayres JG, Nutt DJ, Kerr JR. Microbial infections in eight genomic subtypes of chronic fatigue syndrome/myalgic encephalomyelitis. J Clin Pathol. 2010;63:156–64.PubMedView ArticlePubMed CentralGoogle Scholar
- Wagner M, Krueger GR, Ablashi D, Whitman JE. Chronic fatigue syndrome (CFS): a critical evaluation of testing for active human herpesvirus-6 (HHV-6) infection. J Chronic Fatigue Syndr. 1996;2:3–16.View ArticleGoogle Scholar
- Hickie I, Davenport T, Wakefield D, Vollmer-Conna U, Cameron B, Vernon SD, Reeves WC, Lloyd A. Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study. BMJ. 2006;333:575.PubMedPubMed CentralView ArticleGoogle Scholar
- Cameron B, Flamand L, Juwana H, Middeldorp J, Naing Z, Rawlinson W, Ablashi D, Lloyd A. Serological and virological investigation of the role of the herpesviruses EBV, CMV and HHV-6 in post-infective fatigue syndrome. J Med Virol. 2010;82:1684–8.PubMedView ArticlePubMed CentralGoogle Scholar
- Lerner AM, Ariza ME, Williams M, Jason L, Beqaj S, Fitzgerald JT, Lemeshow S, Glaser R. Antibody to Epstein–Barr virus deoxyuridine triphosphate nucleotidohydrolase and deoxyribonucleotide polymerase in a chronic fatigue syndrome subset. PLoS ONE. 2012;7:e47891.PubMedPubMed CentralView ArticleGoogle Scholar
- Halpin P, Williams MV, Klimas NG, Fletcher MA, Barnes Z, Ariza ME. Myalgic encephalomyelitis/chronic fatigue syndrome and gulf war illness patients exhibit increased humoral responses to the herpesviruses-encoded dUTPase: implications in disease pathophysiology. J Med Virol. 2017;89:1636–45.PubMedPubMed CentralView ArticleGoogle Scholar
- Lerner AM, Beqaj SH, Deeter RG, Fitzgerald JT. IgM serum antibodies to human cytomegalovirus nonstructural gene products p52 and CM2(UL44 and UL57) are uniquely present in a subset of patients with chronic fatigue syndrome. In Vivo. 2002;16:153–9.PubMedPubMed CentralGoogle Scholar
- Rabausch-Starz I, Schwaiger A, Grunewald K, Muller-Hermelink HK, Neu N. Persistence of virus and viral genome in myocardium after coxsackievirus B3-induced murine myocarditis. Clin Exp Immunol. 1994;96:69–74.PubMedPubMed CentralView ArticleGoogle Scholar
- Andreoletti L, Hober D, Becquart P, Belaich S, Copin MC, Lambert V, Wattre P. Experimental CVB3-induced chronic myocarditis in two murine strains: evidence of interrelationships between virus replication and myocardial damage in persistent cardiac infection. J Med Virol. 1997;52:206–14.PubMedView ArticlePubMed CentralGoogle Scholar
- Kandolf R, Sauter M, Aepinus C, Schnorr JJ, Selinka HC, Klingel K. Mechanisms and consequences of enterovirus persistence in cardiac myocytes and cells of the immune system. Virus Res. 1999;62:149–58.PubMedView ArticlePubMed CentralGoogle Scholar
- Frisk G. Mechanisms of chronic enteroviral persistence in tissue. Curr Opin Infect Dis. 2001;14:251–6.PubMedView ArticlePubMed CentralGoogle Scholar
- Clements GB, McGarry F, Nairn C, Galbraith DN. Detection of enterovirus-specific RNA in serum: the relationship to chronic fatigue. J Med Virol. 1995;45:156–61.PubMedView ArticlePubMed CentralGoogle Scholar
- Nairn C, Galbraith DN, Clements GB. Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients. J Med Virol. 1995;46:310–3.PubMedView ArticlePubMed CentralGoogle Scholar
- Gow JW, Behan WM, Clements GB, Woodall C, Riding M, Behan PO. Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome. BMJ. 1991;302:692–6.PubMedPubMed CentralView ArticleGoogle Scholar
- Lane RJ, Soteriou BA, Zhang H, Archard LC. Enterovirus related metabolic myopathy: a postviral fatigue syndrome. J Neurol Neurosurg Psychiatry. 2003;74:1382–6.PubMedPubMed CentralView ArticleGoogle Scholar
- Bowles NE, Bayston TA, Zhang HY, Doyle D, Lane RJ, Cunningham L, Archard LC. Persistence of enterovirus RNA in muscle biopsy samples suggests that some cases of chronic fatigue syndrome result from a previous, inflammatory viral myopathy. J Med. 1993;24:145–60.PubMedPubMed CentralGoogle Scholar
- Cunningham L, Bowles NE, Lane RJ, Dubowitz V, Archard LC. Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA. J Gen Virol. 1990;71(Pt 6):1399–402.PubMedView ArticlePubMed CentralGoogle Scholar
- Douche-Aourik F, Berlier W, Feasson L, Bourlet T, Harrath R, Omar S, Grattard F, Denis C, Pozzetto B. Detection of enterovirus in human skeletal muscle from patients with chronic inflammatory muscle disease or fibromyalgia and healthy subjects. J Med Virol. 2003;71:540–7.PubMedView ArticlePubMed CentralGoogle Scholar
- Chia JK, Chia AY. Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach. J Clin Pathol. 2008;61:43–8.PubMedView ArticlePubMed CentralGoogle Scholar
- Chia J, Chia A, Voeller M, Lee T, Chang R. Acute enterovirus infection followed by myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and viral persistence. J Clin Pathol. 2010;63:165–8.PubMedView ArticlePubMed CentralGoogle Scholar
- Galbraith DN, Nairn C, Clements GB. Phylogenetic analysis of short enteroviral sequences from patients with chronic fatigue syndrome. J Gen Virol. 1995;76(Pt 7):1701–7.PubMedView ArticleGoogle Scholar
- Galbraith DN, Nairn C, Clements GB. Evidence for enteroviral persistence in humans. J Gen Virol. 1997;78(Pt 2):307–12.PubMedView ArticleGoogle Scholar
- Chia JK, Chia AY. Ribavirin and interferon-a for the treatment of patients with chronic fatigue syndrome associated with persistent coxsackievirus b infection: a preliminary observation. J Appl Res. 2004;4:286–92.Google Scholar
- Swanink CM, Melchers WJ, van der Meer JW, Vercoulen JH, Bleijenberg G, Fennis JF, Galama JM. Enteroviruses and the chronic fatigue syndrome. Clin Infect Dis. 1994;19:860–4.PubMedView ArticlePubMed CentralGoogle Scholar
- Lindh G, Samuelson A, Hedlund KO, Evengard B, Lindquist L, Ehrnst A. No findings of enteroviruses in Swedish patients with chronic fatigue syndrome. Scand J Infect Dis. 1996;28:305–7.PubMedView ArticleGoogle Scholar
- McArdle A, McArdle F, Jackson MJ, Page SF, Fahal I, Edwards RH. Investigation by polymerase chain reaction of enteroviral infection in patients with chronic fatigue syndrome. Clin Sci (Lond). 1996;90:295–300.View ArticleGoogle Scholar
- Gow JW, Behan WM, Simpson K, McGarry F, Keir S, Behan PO. Studies on enterovirus in patients with chronic fatigue syndrome. Clin Infect Dis. 1994;18(Suppl 1):S126–9.PubMedView ArticlePubMed CentralGoogle Scholar
- Cossart YE, Field AM, Cant B, Widdows D. Parvovirus-like particles in human sera. Lancet. 1975;1:72–3.PubMedView ArticlePubMed CentralGoogle Scholar
- Pattison JR, Jones SE, Hodgson J, Davis LR, White JM, Stroud CE, Murtaza L. Parvovirus infections and hypoplastic crisis in sickle-cell anaemia. Lancet. 1981;1:664–5.PubMedView ArticleGoogle Scholar
- Kerr JR. Pathogenesis of human parvovirus B19 in rheumatic disease. Ann Rheum Dis. 2000;59:672–83.PubMedPubMed CentralView ArticleGoogle Scholar
- Kerr JR. The role of parvovirus B19 in the pathogenesis of autoimmunity and autoimmune disease. J Clin Pathol. 2016;69:279–91.PubMedView ArticlePubMed CentralGoogle Scholar
- Barah F, Whiteside S, Batista S, Morris J. Neurological aspects of human parvovirus B19 infection: a systematic review. Rev Med Virol. 2014;24:154–68.PubMedPubMed CentralView ArticleGoogle Scholar
- Kerr JR, Tyrrell DA. Cytokines in parvovirus B19 infection as an aid to understanding chronic fatigue syndrome. Curr Pain Headache Rep. 2003;7:333–41.PubMedView ArticleGoogle Scholar
- Ilaria RL Jr, Komaroff AL, Fagioli LR, Moloney WC, True CA, Naides SJ. Absence of parvovirus B19 infection in chronic fatigue syndrome. Arthritis Rheum. 1995;38:638–41.PubMedView ArticleGoogle Scholar
- Kerr JR, Mattey DL. Preexisting psychological stress predicts acute and chronic fatigue and arthritis following symptomatic parvovirus B19 infection. Clin Infect Dis. 2008;46:e83–7.PubMedView ArticleGoogle Scholar
- Kato YH, Yamate M, Tsujikawa M, Nishigaki H, Tanaka Y, Yunoki M, Kuratsune H, Watanabe Y, Ikuta K. No apparent difference in the prevalence of parvovirus B19 infection between chronic fatigue syndrome patients and healthy controls in Japan. J Clin Virol. 2009;44:246–7.PubMedView ArticleGoogle Scholar
- Kerr JR, Gough J, Richards SC, Main J, Enlander D, McCreary M, Komaroff AL, Chia JK. Antibody to parvovirus B19 nonstructural protein is associated with chronic arthralgia in patients with chronic fatigue syndrome/myalgic encephalomyelitis. J Gen Virol. 2010;91:893–7.PubMedView ArticleGoogle Scholar
- Urisman A, Molinaro RJ, Fischer N, Plummer SJ, Casey G, Klein EA, Malathi K, Magi-Galluzzi C, Tubbs RR, Ganem D, et al. Identification of a novel Gammaretrovirus in prostate tumors of patients homozygous for R462Q RNASEL variant. PLoS Pathog. 2006;2:e25.PubMedPubMed CentralView ArticleGoogle Scholar
- Paprotka T, Delviks-Frankenberry KA, Cingoz O, Martinez A, Kung HJ, Tepper CG, Hu WS, Fivash MJ Jr, Coffin JM, Pathak VK. Recombinant origin of the retrovirus XMRV. Science. 2011;333:97–101.PubMedPubMed CentralView ArticleGoogle Scholar
- Demettre E, Bastide L, D’Haese A, De Smet K, De Meirleir K, Tiev KP, Englebienne P, Lebleu B. Ribonuclease L proteolysis in peripheral blood mononuclear cells of chronic fatigue syndrome patients. J Biol Chem. 2002;277:35746–51.PubMedView ArticleGoogle Scholar
- Lombardi VC, Ruscetti FW, Das Gupta J, Pfost MA, Hagen KS, Peterson DL, Ruscetti SK, Bagni RK, Petrow-Sadowski C, Gold B, et al. Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. Science. 2009;326:585–9.PubMedView ArticleGoogle Scholar
- Alberts B. Retraction. Science. 2011;334:1636.PubMedView ArticleGoogle Scholar
- Lo SC, Pripuzova N, Li B, Komaroff AL, Hung GC, Wang R, Alter HJ. Detection of MLV-related virus gene sequences in blood of patients with chronic fatigue syndrome and healthy blood donors. Proc Natl Acad Sci USA. 2010;107:15874–9.PubMedView ArticleGoogle Scholar
- Erlwein O, Kaye S, McClure MO, Weber J, Wills G, Collier D, Wessely S, Cleare A. Failure to detect the novel retrovirus XMRV in chronic fatigue syndrome. PLoS ONE. 2010;5:e8519.PubMedPubMed CentralView ArticleGoogle Scholar
- Hohn O, Strohschein K, Brandt AU, Seeher S, Klein S, Kurth R, Paul F, Meisel C, Scheibenbogen C, Bannert N. No evidence for XMRV in German CFS and MS patients with fatigue despite the ability of the virus to infect human blood cells in vitro. PLoS ONE. 2010;5:e15632.PubMedPubMed CentralView ArticleGoogle Scholar
- Hong P, Li J, Li Y. Failure to detect Xenotropic murine leukaemia virus-related virus in Chinese patients with chronic fatigue syndrome. Virol J. 2010;7:224.PubMedPubMed CentralView ArticleGoogle Scholar
- Switzer WM, Jia H, Hohn O, Zheng H, Tang S, Shankar A, Bannert N, Simmons G, Hendry RM, Falkenberg VR, et al. Absence of evidence of Xenotropic murine leukemia virus-related virus infection in persons with chronic fatigue syndrome and healthy controls in the United States. Retrovirology. 2010;7:57.PubMedPubMed CentralView ArticleGoogle Scholar
- Elfaitouri A, Shao X, Mattsson Ulfstedt J, Muradrasoli S, Bolin Wiener A, Golbob S, Ohrmalm C, Matousek M, Zachrisson O, Gottfries CG, Blomberg J. Murine gammaretrovirus group G3 was not found in Swedish patients with myalgic encephalomyelitis/chronic fatigue syndrome and fibromyalgia. PLoS ONE. 2011;6:e24602.PubMedPubMed CentralView ArticleGoogle Scholar
- Groom HC, Boucherit VC, Makinson K, Randal E, Baptista S, Hagan S, Gow JW, Mattes FM, Breuer J, Kerr JR, et al. Absence of Xenotropic murine leukaemia virus-related virus in UK patients with chronic fatigue syndrome. Retrovirology. 2010;7:10.PubMedPubMed CentralView ArticleGoogle Scholar
- Furuta RA, Miyazawa T, Sugiyama T, Kuratsune H, Ikeda Y, Sato E, Misawa N, Nakatomi Y, Sakuma R, Yasui K, et al. No association of Xenotropic murine leukemia virus-related virus with prostate cancer or chronic fatigue syndrome in Japan. Retrovirology. 2011;8:20.PubMedPubMed CentralView ArticleGoogle Scholar
- Satterfield BC, Garcia RA, Jia H, Tang S, Zheng H, Switzer WM. Serologic and PCR testing of persons with chronic fatigue syndrome in the United States shows no association with xenotropic or polytropic murine leukemia virus-related viruses. Retrovirology. 2011;8:12.PubMedPubMed CentralView ArticleGoogle Scholar
- Steffen I, Tyrrell DL, Stein E, Montalvo L, Lee TH, Zhou Y, Lu K, Switzer WM, Tang S, Jia H, et al. No evidence for XMRV nucleic acids, infectious virus or anti-XMRV antibodies in Canadian patients with chronic fatigue syndrome. PLoS ONE. 2011;6:e27870.PubMedPubMed CentralView ArticleGoogle Scholar
- van Kuppeveld FJ, de Jong AS, Lanke KH, Verhaegh GW, Melchers WJ, Swanink CM, Bleijenberg G, Netea MG, Galama JM, van der Meer JW. Prevalence of Xenotropic murine leukaemia virus-related virus in patients with chronic fatigue syndrome in the Netherlands: retrospective analysis of samples from an established cohort. BMJ. 2010;340:c1018.PubMedPubMed CentralView ArticleGoogle Scholar
- Alter HJ, Mikovits JA, Switzer WM, Ruscetti FW, Lo SC, Klimas N, Komaroff AL, Montoya JG, Bateman L, Levine S, et al. A multicenter blinded analysis indicates no association between chronic fatigue syndrome/myalgic encephalomyelitis and either Xenotropic murine leukemia virus-related virus or polytropic murine leukemia virus. MBio. 2012;3:e00266.PubMedPubMed CentralView ArticleGoogle Scholar
- Rasa S, Nora-Krukle Z, Chapenko S, Krumina A, Roga S, Murovska M. No evidence of XMRV provirus sequences in patients with myalgic encephalomyelitis/chronic fatigue syndrome and individuals with unspecified encephalopathy. New Microbiol. 2014;37:17–24.PubMedGoogle Scholar
- Panelli S, Lorusso L, Balestrieri A, Lupo G, Capelli E. XMRV and Public Health: the retroviral genome is not a suitable template for diagnostic pcr, and its association with myalgic encephalomyelitis/chronic fatigue syndrome appears unreliable. Front Public Health. 2017;5:108.PubMedPubMed CentralView ArticleGoogle Scholar
- Knox K, Carrigan D, Simmons G, Teque F, Zhou Y, Hackett J Jr, Qiu X, Luk KC, Schochetman G, Knox A, et al. No evidence of murine-like gammaretroviruses in CFS patients previously identified as XMRV-infected. Science. 2011;333:94–7.PubMedView ArticleGoogle Scholar
- Smith RA. Contamination of clinical specimens with MLV-encoding nucleic acids: implications for XMRV and other candidate human retroviruses. Retrovirology. 2010;7:112.PubMedPubMed CentralView ArticleGoogle Scholar
- Katzourakis A, Hue S, Kellam P, Towers GJ. Phylogenetic analysis of murine leukemia virus sequences from longitudinally sampled chronic fatigue syndrome patients suggests PCR contamination rather than viral evolution. J Virol. 2011;85:10909–13.PubMedPubMed CentralView ArticleGoogle Scholar
- Shin CH, Bateman L, Schlaberg R, Bunker AM, Leonard CJ, Hughen RW, Light AR, Light KC, Singh IR. Absence of XMRV retrovirus and other murine leukemia virus-related viruses in patients with chronic fatigue syndrome. J Virol. 2011;85:7195–202.PubMedPubMed CentralView ArticleGoogle Scholar
- Irlbeck DM, Vernon SD, McCleary KK, Bateman L, Klimas NG, Lapp CW, Peterson DL, Brown JR, Remlinger KS, Wilfret DA, Gerondelis P. No association found between the detection of either Xenotropic murine leukemia virus-related virus or polytropic murine leukemia virus and chronic fatigue syndrome in a blinded, multi-site, prospective study by the establishment and use of the SolveCFS BioBank. BMC Res Notes. 2014;7:461.PubMedPubMed CentralView ArticleGoogle Scholar
- Kearney MF, Spindler J, Wiegand A, Shao W, Anderson EM, Maldarelli F, Ruscetti FW, Mellors JW, Hughes SH, Le Grice SF, Coffin JM. Multiple sources of contamination in samples from patients reported to have XMRV infection. PLoS ONE. 2012;7:e30889.PubMedPubMed CentralView ArticleGoogle Scholar
- Johnson AD, Cohn CS. Xenotropic murine leukemia virus-related virus (XMRV) and the safety of the blood supply. Clin Microbiol Rev. 2016;29:749–57.PubMedPubMed CentralView ArticleGoogle Scholar
- Gow JW, Simpson K, Schliephake A, Behan WM, Morrison LJ, Cavanagh H, Rethwilm A, Behan PO. Search for retrovirus in the chronic fatigue syndrome. J Clin Pathol. 1992;45:1058–61.PubMedPubMed CentralView ArticleGoogle Scholar
- Khan AS, Heneine WM, Chapman LE, Gary HE Jr, Woods TC, Folks TM, Schonberger LB. Assessment of a retrovirus sequence and other possible risk factors for the chronic fatigue syndrome in adults. Ann Intern Med. 1993;118:241–5.PubMedView ArticleGoogle Scholar
- Selden SM, Cameron AS. Changing epidemiology of Ross River virus disease in South Australia. Med J Aust. 1996;165:313–7.PubMedGoogle Scholar
- Lidbury BA, Mahalingam S. Specific ablation of antiviral gene expression in macrophages by antibody-dependent enhancement of Ross River virus infection. J Virol. 2000;74:8376–81.PubMedPubMed CentralView ArticleGoogle Scholar
- Mahalingam S, Lidbury BA. Suppression of lipopolysaccharide-induced antiviral transcription factor (STAT-1 and NF-kappa B) complexes by antibody-dependent enhancement of macrophage infection by Ross River virus. Proc Natl Acad Sci USA. 2002;99:13819–24.PubMedView ArticleGoogle Scholar
- Vollmer-Conna U, Fazou C, Cameron B, Li H, Brennan C, Luck L, Davenport T, Wakefield D, Hickie I, Lloyd A. Production of pro-inflammatory cytokines correlates with the symptoms of acute sickness behaviour in humans. Psychol Med. 2004;34:1289–97.PubMedView ArticleGoogle Scholar
- Galbraith S, Cameron B, Li H, Lau D, Vollmer-Conna U, Lloyd AR. Peripheral blood gene expression in postinfective fatigue syndrome following from three different triggering infections. J Infect Dis. 2011;204:1632–40.PubMedView ArticleGoogle Scholar
- Cvejic E, Lemon J, Hickie IB, Lloyd AR, Vollmer-Conna U. Neurocognitive disturbances associated with acute infectious mononucleosis, Ross River fever and Q fever: a preliminary investigation of inflammatory and genetic correlates. Brain Behav Immun. 2014;36:207–14.PubMedView ArticleGoogle Scholar
- Nijs J, Fremont M. Intracellular immune dysfunction in myalgic encephalomyelitis/chronic fatigue syndrome: state of the art and therapeutic implications. Expert Opin Ther Targets. 2008;12:281–9.PubMedView ArticleGoogle Scholar
- Broderick G, Fuite J, Kreitz A, Vernon SD, Klimas N, Fletcher MA. A formal analysis of cytokine networks in chronic fatigue syndrome. Brain Behav Immun. 2010;24:1209–17.PubMedPubMed CentralView ArticleGoogle Scholar
- Glassford JA. The neuroinflammatory etiopathology of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Front Physiol. 2017;8:88.PubMedPubMed CentralView ArticleGoogle Scholar
- Sairenji T, Nagata K. Viral infections in chronic fatigue syndrome. Nihon Rinsho. 2007;65:991–6.PubMedGoogle Scholar
- Patarca R, Sandler D, Walling J, Lunn BC, Fletcher MA. Assessment of immune mediator expression levels in biological fluids and cells: a critical appraisal. Crit Rev Oncog. 1995;6:117–49.PubMedGoogle Scholar
- Maes M, Twisk FN, Kubera M, Ringel K. Evidence for inflammation and activation of cell-mediated immunity in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): increased interleukin-1, tumor necrosis factor-alpha, PMN-elastase, lysozyme and neopterin. J Affect Disord. 2012;136:933–9.PubMedView ArticleGoogle Scholar
- Yasui M, Yoshimura T, Takeuchi S, Tokizane K, Tsuda M, Inoue K, Kiyama H. A chronic fatigue syndrome model demonstrates mechanical allodynia and muscular hyperalgesia via spinal microglial activation. Glia. 2014;62:1407–17.PubMedView ArticleGoogle Scholar
- Tejada-Simon MV, Zang YC, Hong J, Rivera VM, Zhang JZ. Cross-reactivity with myelin basic protein and human herpesvirus-6 in multiple sclerosis. Ann Neurol. 2003;53:189–97.PubMedView ArticleGoogle Scholar
- Peng N, Yang X, Zhu C, Zhou L, Yu H, Li M, Lin Y, Wang X, Li Q, She Y, et al. MicroRNA-302 cluster downregulates enterovirus 71-induced innate immune response by targeting KPNA2. J Immunol. 2018;201:145–56.PubMedView ArticleGoogle Scholar
- Lind K, Svedin E, Domsgen E, Kapell S, Laitinen O, Moll M, Flodstrom-Tullberg M. Coxsackievirus counters the host innate immune response by blocking type III interferon expression. J Gen Virol. 2016;97:1–12.PubMedView ArticleGoogle Scholar
- Pathinayake PS, Hsu AC, Wark PA. Innate immunity and immune evasion by enterovirus 71. Viruses. 2015;7:6613–30.PubMedPubMed CentralView ArticleGoogle Scholar
- Rizzo R, Soffritti I, D’Accolti M, Bortolotti D, Di Luca D, Caselli E. HHV-6A/6B infection of NK cells modulates the expression of mirnas and transcription factors potentially associated to impaired NK activity. Front Microbiol. 2017;8:2143.PubMedPubMed CentralView ArticleGoogle Scholar
- Prusty BK, Gulve N, Chowdhury SR, Schuster M, Strempel S, Descamps V, Rudel T. HHV-6 encoded small non-coding RNAs define an intermediate and early stage in viral reactivation. npj Genomic Med. 2018;3:25.View ArticleGoogle Scholar
- Schmiedel D, Tai J, Levi-Schaffer F, Dovrat S, Mandelboim O. Human herpesvirus 6B downregulates expression of activating ligands during lytic infection to escape elimination by natural killer cells. J Virol. 2016;90:9608–17.PubMedPubMed CentralView ArticleGoogle Scholar
- Fan C, Tang Y, Wang J, Xiong F, Guo C, Wang Y, Xiang B, Zhou M, Li X, Wu X, et al. The emerging role of Epstein–Barr virus encoded microRNAs in nasopharyngeal carcinoma. J Cancer. 2018;9:2852–64.PubMedPubMed CentralView ArticleGoogle Scholar
- Hardcastle SL, Brenu EW, Johnston S, Nguyen T, Huth T, Ramos S, Staines D, Marshall-Gradisnik S. Longitudinal analysis of immune abnormalities in varying severities of chronic fatigue syndrome/myalgic encephalomyelitis patients. J Transl Med. 2015;13:299.PubMedPubMed CentralView ArticleGoogle Scholar
- Lusso P. HHV-6 and the immune system: mechanisms of immunomodulation and viral escape. J Clin Virol. 2006;37(Suppl 1):S4–10.PubMedView ArticleGoogle Scholar
- Sin SH, Dittmer DP. Cytokine homologs of human gammaherpesviruses. J Interferon Cytokine Res. 2012;32:53–9.PubMedPubMed CentralView ArticleGoogle Scholar
- Odom CI, Gaston DC, Markert JM, Cassady KA. Human herpesviridae methods of natural killer cell evasion. Adv Virol. 2012;2012:359869.PubMedPubMed CentralView ArticleGoogle Scholar
- Kemball CC, Harkins S, Whitmire JK, Flynn CT, Feuer R, Whitton JL. Coxsackievirus B3 inhibits antigen presentation in vivo, exerting a profound and selective effect on the MHC class I pathway. PLoS Pathog. 2009;5:e1000618.PubMedPubMed CentralView ArticleGoogle Scholar
- Kemball CC, Alirezaei M, Whitton JL. Type B coxsackieviruses and their interactions with the innate and adaptive immune systems. Future Microbiol. 2010;5:1329–47.PubMedPubMed CentralView ArticleGoogle Scholar
- Schneider CL, Hudson AW. The human herpesvirus-7 (HHV-7) U21 immunoevasin subverts NK-mediated cytoxicity through modulation of MICA and MICB. PLoS Pathog. 2011;7:e1002362.PubMedPubMed CentralView ArticleGoogle Scholar
- Nastke MD, Becerra A, Yin L, Dominguez-Amorocho O, Gibson L, Stern LJ, Calvo-Calle JM. Human CD4+ T cell response to human herpesvirus 6. J Virol. 2012;86:4776–92.PubMedPubMed CentralView ArticleGoogle Scholar
- Kerr JR, Barah F, Mattey DL, Laing I, Hopkins SJ, Hutchinson IV, Tyrrell DA. Circulating tumour necrosis factor-alpha and interferon-gamma are detectable during acute and convalescent parvovirus B19 infection and are associated with prolonged and chronic fatigue. J Gen Virol. 2001;82:3011–9.PubMedView ArticleGoogle Scholar
- Appel S, Chapman J, Shoenfeld Y. Infection and vaccination in chronic fatigue syndrome: myth or reality? Autoimmunity. 2007;40:48–53.PubMedView ArticlePubMed CentralGoogle Scholar
- Matano S, Kinoshita H, Tanigawa K, Terahata S, Sugimoto T. Acute parvovirus B19 infection mimicking chronic fatigue syndrome. Intern Med. 2003;42:903–5.PubMedView ArticlePubMed CentralGoogle Scholar
- Chehadeh W, Alkhabbaz M. Differential TLR7-mediated expression of proinflammatory and antiviral cytokines in response to laboratory and clinical enterovirus strains. Virus Res. 2013;174:88–94.PubMedView ArticleGoogle Scholar
- Shang W, Qian S, Fang L, Han Y, Zheng C. Association study of inflammatory cytokine and chemokine expression in hand foot and mouth disease. Oncotarget. 2017;8:79425–32.PubMedPubMed CentralGoogle Scholar
- De Pelsmaeker S, Romero N, Vitale M, Favoreel HW. Herpesvirus evasion of natural killer cells. J Virol. 2018;92:e02105.PubMedView ArticlePubMed CentralGoogle Scholar
- Filler K, Lyon D, Bennett J, McCain N, Elswick R, Lukkahatai N, Saligan LN. Association of mitochondrial dysfunction and fatigue: a review of the literature. BBA Clin. 2014;1:12–23.PubMedPubMed CentralView ArticleGoogle Scholar
- Myhill S, Booth NE, McLaren-Howard J. Chronic fatigue syndrome and mitochondrial dysfunction. Int J Clin Exp Med. 2009;2:1–16.PubMedPubMed CentralGoogle Scholar
- Booth NE, Myhill S, McLaren-Howard J. Mitochondrial dysfunction and the pathophysiology of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Int J Clin Exp Med. 2012;5:208–20.PubMedPubMed CentralGoogle Scholar
- Meeus M, Nijs J, Hermans L, Goubert D, Calders P. The role of mitochondrial dysfunctions due to oxidative and nitrosative stress in the chronic pain or chronic fatigue syndromes and fibromyalgia patients: peripheral and central mechanisms as therapeutic targets? Expert Opin Ther Targets. 2013;17:1081–9.PubMedView ArticlePubMed CentralGoogle Scholar
- Vogt H, Ulvestad E, Wyller VB. Metabolic features of chronic fatigue syndrome revisited. Proc Natl Acad Sci USA. 2016;113:E7140–1.PubMedView ArticlePubMed CentralGoogle Scholar
- Naviaux RK, Naviaux JC, Li K, Bright AT, Alaynick WA, Wang L, Baxter A, Nathan N, Anderson W, Gordon E. Metabolic features of chronic fatigue syndrome. Proc Natl Acad Sci USA. 2016;113:E5472–80.PubMedView ArticlePubMed CentralGoogle Scholar
- Hanson MR, Gu Z, Keinan A, Ye K, Germain A, Billing-Ross P. Association of mitochondrial DNA variants with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) symptoms. J Transl Med. 2016;14:342.PubMedPubMed CentralView ArticleGoogle Scholar
- Billing-Ross P, Germain A, Ye K, Keinan A, Gu Z, Hanson MR. Mitochondrial DNA variants correlate with symptoms in myalgic encephalomyelitis/chronic fatigue syndrome. J Transl Med. 2016;14:19.PubMedPubMed CentralView ArticleGoogle Scholar
- Murata T, Goshima F, Daikoku T, Inagaki-Ohara K, Takakuwa H, Kato K, Nishiyama Y. Mitochondrial distribution and function in herpes simplex virus-infected cells. J Gen Virol. 2000;81:401–6.PubMedView ArticleGoogle Scholar
- Aubert M, Chen Z, Lang R, Dang CH, Fowler C, Sloan DD, Jerome KR. The antiapoptotic herpes simplex virus glycoprotein J localizes to multiple cellular organelles and induces reactive oxygen species formation. J Virol. 2008;82:617–29.PubMedView ArticleGoogle Scholar
- Saffran HA, Pare JM, Corcoran JA, Weller SK, Smiley JR. Herpes simplex virus eliminates host mitochondrial DNA. EMBO Rep. 2007;8:188–93.PubMedView ArticleGoogle Scholar
- Vernon SD, Whistler T, Cameron B, Hickie IB, Reeves WC, Lloyd A. Preliminary evidence of mitochondrial dysfunction associated with post-infective fatigue after acute infection with Epstein Barr virus. BMC Infect Dis. 2006;6:15.PubMedPubMed CentralView ArticleGoogle Scholar
- Pal AD, Basak NP, Banerjee AS, Banerjee S. Epstein–Barr virus latent membrane protein-2A alters mitochondrial dynamics promoting cellular migration mediated by Notch signaling pathway. Carcinogenesis. 2014;35:1592–601.PubMedView ArticleGoogle Scholar
- Wiedmer A, Wang P, Zhou J, Rennekamp AJ, Tiranti V, Zeviani M, Lieberman PM. Epstein–Barr virus immediate-early protein Zta co-opts mitochondrial single-stranded DNA binding protein to promote viral and inhibit mitochondrial DNA replication. J Virol. 2008;82:4647–55.PubMedPubMed CentralView ArticleGoogle Scholar
- Yeo WM, Isegawa Y, Chow VT. The U95 protein of human herpesvirus 6B interacts with human GRIM-19: silencing of U95 expression reduces viral load and abrogates loss of mitochondrial membrane potential. J Virol. 2008;82:1011–20.PubMedView ArticleGoogle Scholar
- Prusty BK, Bohme L, Bergmann B, Siegl C, Krause E, Mehlitz A, Rudel T. Imbalanced oxidative stress causes chlamydial persistence during non-productive human herpes virus co-infection. PLoS ONE. 2012;7:e47427.PubMedPubMed CentralView ArticleGoogle Scholar
- Li L, Chi J, Zhou F, Guo D, Wang F, Liu G, Zhang C, Yao K. Human herpesvirus 6A induces apoptosis of HSB-2 cells via a mitochondrion-related caspase pathway. J Biomed Res. 2010;24:444–51.PubMedPubMed CentralView ArticleGoogle Scholar
- Lee YL, Liu CE, Cho WL, Kuo CL, Cheng WL, Huang CS, Liu CS. Presence of cytomegalovirus DNA in leucocytes is associated with increased oxidative stress and subclinical atherosclerosis in healthy adults. Biomarkers. 2014;19:109–13.PubMedView ArticlePubMed CentralGoogle Scholar
- Hwang KY, Choi YB. Modulation of mitochondrial antiviral signaling by human herpesvirus 8 interferon regulatory factor 1. J Virol. 2016;90:506–20.PubMedView ArticlePubMed CentralGoogle Scholar
- Nykky J, Vuento M, Gilbert L. Role of mitochondria in parvovirus pathology. PLoS ONE. 2014;9:e86124.PubMedPubMed CentralView ArticleGoogle Scholar
- Zhao X, Xiang H, Bai X, Fei N, Huang Y, Song X, Zhang H, Zhang L, Tong D. Porcine parvovirus infection activates mitochondria-mediated apoptotic signaling pathway by inducing ROS accumulation. Virol J. 2016;13:26.PubMedPubMed CentralView ArticleGoogle Scholar
- Gupta SK, Sahoo AP, Rosh N, Gandham RK, Saxena L, Singh AK, Harish DR, Tiwari AK. Canine parvovirus NS1 induced apoptosis involves mitochondria, accumulation of reactive oxygen species and activation of caspases. Virus Res. 2016;213:46–61.PubMedView ArticlePubMed CentralGoogle Scholar
- Cheng ML, Weng SF, Kuo CH, Ho HY. Enterovirus 71 induces mitochondrial reactive oxygen species generation that is required for efficient replication. PLoS ONE. 2014;9:e113234.PubMedPubMed CentralView ArticleGoogle Scholar
- Blomberg J, Gottfries CG, Elfaitouri A, Rizwan M, Rosen A. Infection elicited autoimmunity and myalgic encephalomyelitis/chronic fatigue syndrome: an explanatory model. Front Immunol. 2018;9:229.PubMedPubMed CentralView ArticleGoogle Scholar
- Montoya JG, Kogelnik AM, Bhangoo M, Lunn MR, Flamand L, Merrihew LE, Watt T, Kubo JT, Paik J, Desai M. Randomized clinical trial to evaluate the efficacy and safety of valganciclovir in a subset of patients with chronic fatigue syndrome. J Med Virol. 2013;85:2101–9.PubMedView ArticlePubMed CentralGoogle Scholar
- Fluge O, Risa K, Lunde S, Alme K, Rekeland IG, Sapkota D, Kristoffersen EK, Sorland K, Bruland O, Dahl O, Mella O. B-lymphocyte depletion in myalgic encephalopathy/chronic fatigue syndrome. an open-label phase II study with rituximab maintenance treatment. PLoS ONE. 2015;10:e0129898.PubMedPubMed CentralView ArticleGoogle Scholar
- Scheibenbogen C, Loebel M, Freitag H, Krueger A, Bauer S, Antelmann M, Doehner W, Scherbakov N, Heidecke H, Reinke P, et al. Immunoadsorption to remove ss2 adrenergic receptor antibodies in chronic fatigue syndrome CFS/ME. PLoS ONE. 2018;13:e0193672.PubMedPubMed CentralView ArticleGoogle Scholar
- Engelmann I, Alidjinou EK, Bertin A, Bossu J, Villenet C, Figeac M, Sane F, Hober D. Persistent coxsackievirus B4 infection induces microRNA dysregulation in human pancreatic cells. Cell Mol Life Sci. 2017;74:3851–61.PubMedView ArticlePubMed CentralGoogle Scholar
- Burg AR, Das S, Padgett LE, Koenig ZE, Tse HM. Superoxide production by NADPH oxidase intensifies macrophage antiviral responses during diabetogenic coxsackievirus infection. J Immunol. 2018;200:61–70.PubMedView ArticlePubMed CentralGoogle Scholar
- Lind K, Huhn MH, Flodstrom-Tullberg M. Immunology in the clinic review series; focus on type 1 diabetes and viruses: the innate immune response to enteroviruses and its possible role in regulating type 1 diabetes. Clin Exp Immunol. 2012;168:30–8.PubMedPubMed CentralView ArticleGoogle Scholar
- Grammatikos AP, Tsokos GC. Immunodeficiency and autoimmunity: lessons from systemic lupus erythematosus. Trends Mol Med. 2012;18:101–8.PubMedView ArticleGoogle Scholar
- Dotta F, Censini S, van Halteren AG, Marselli L, Masini M, Dionisi S, Mosca F, Boggi U, Muda AO, Del Prato S, et al. Coxsackie B4 virus infection of beta cells and natural killer cell insulitis in recent-onset type 1 diabetic patients. Proc Natl Acad Sci U S A. 2007;104:5115–20.PubMedPubMed CentralView ArticleGoogle Scholar
- Wagner AD, Goronzy JJ, Matteson EL, Weyand CM. Systemic monocyte and T-cell activation in a patient with human parvovirus B19 infection. Mayo Clin Proc. 1995;70:261–5.PubMedView ArticleGoogle Scholar
- Xie J, Jiao Y, Qiu Z, Li Q, Li T. Significant elevation of B cells at the acute stage in enterovirus 71-infected children with central nervous system involvement. Scand J Infect Dis. 2010;42:931–5.PubMedView ArticleGoogle Scholar
- Caselli E, D’Accolti M, Soffritti I, Zatelli MC, Rossi R, Degli Uberti E, Di Luca D. HHV-6A in vitro infection of thyrocytes and T cells alters the expression of miRNA associated to autoimmune thyroiditis. Virol J. 2017;14:3.PubMedPubMed CentralView ArticleGoogle Scholar
- Kubo T, Sato K, Kobayashi D, Motegi A, Kobayashi O, Takeshita S, Nonoyama S. A case of HHV-6 associated acute necrotizing encephalopathy with increase of CD56bright NKcells. Scand J Infect Dis. 2006;38:1122–5.PubMedView ArticleGoogle Scholar
- Rizzo R, Zatelli MC, Rotola A, Cassai E, Degli Uberti E, Di Luca D, Caselli E. Increase in peripheral CD3−CD56brightCD16− natural killer cells in Hashimoto’s thyroiditis associated with HHV-6 infection. Adv Exp Med Biol. 2016;897:113–20.PubMedView ArticleGoogle Scholar
- Brenu EW, van Driel ML, Staines DR, Ashton KJ, Hardcastle SL, Keane J, Tajouri L, Peterson D, Ramos SB, Marshall-Gradisnik SM. Longitudinal investigation of natural killer cells and cytokines in chronic fatigue syndrome/myalgic encephalomyelitis. J Transl Med. 2012;10:88.PubMedPubMed CentralView ArticleGoogle Scholar
- Montoya JG, Holmes TH, Anderson JN, Maecker HT, Rosenberg-Hasson Y, Valencia IJ, Chu L, Younger JW, Tato CM, Davis MM. Cytokine signature associated with disease severity in chronic fatigue syndrome patients. Proc Natl Acad Sci USA. 2017;114:E7150–8.PubMedView ArticleGoogle Scholar
- Prinsen H, de Vries IJ, Torensma R, Pots JM, Mulder SF, van Herpen CM, Elving LD, Bleijenberg G, Stelma FF, van Laarhoven HW. Humoral and cellular immune responses after influenza vaccination in patients with chronic fatigue syndrome. BMC Immunol. 2012;13:71.PubMedPubMed CentralView ArticleGoogle Scholar
- Curriu M, Carrillo J, Massanella M, Rigau J, Alegre J, Puig J, Garcia-Quintana AM, Castro-Marrero J, Negredo E, Clotet B, et al. Screening NK-, B- and T-cell phenotype and function in patients suffering from Chronic Fatigue Syndrome. J Transl Med. 2013;11:68.PubMedPubMed CentralView ArticleGoogle Scholar
- Rivas JL, Palencia T, Fernandez G, Garcia M. Association of T and NK Cell Phenotype With the Diagnosis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Front Immunol. 1028;2018:9.Google Scholar
- Harley JB, Chen X, Pujato M, Miller D, Maddox A, Forney C, Magnusen AF, Lynch A, Chetal K, Yukawa M, et al. Transcription factors operate across disease loci, with EBNA2 implicated in autoimmunity. Nat Genet. 2018;50:699–707.PubMedView ArticleGoogle Scholar
- Eriksen W. The spread of EBV to ectopic lymphoid aggregates may be the final common pathway in the pathogenesis of ME/CFS. Med Hypotheses. 2017;102:8–15.PubMedView ArticlePubMed CentralGoogle Scholar
- VanElzakker MB. Chronic fatigue syndrome from vagus nerve infection: a psychoneuroimmunological hypothesis. Med Hypotheses. 2013;81:414–23.PubMedView ArticlePubMed CentralGoogle Scholar
- Nakatomi Y, Mizuno K, Ishii A, Wada Y, Tanaka M, Tazawa S, Onoe K, Fukuda S, Kawabe J, Takahashi K, et al. Neuroinflammation in patients with chronic fatigue syndrome/myalgic encephalomyelitis: an (1)(1)C-(R)-PK11195 PET Study. J Nucl Med. 2014;55:945–50.PubMedView ArticleGoogle Scholar
- Moreno MA, Or-Geva N, Aftab BT, Khanna R, Croze E, Steinman L, Han MH. Molecular signature of Epstein–Barr virus infection in MS brain lesions. Neurol Neuroimmunol Neuroinflamm. 2018;5:e466.PubMedPubMed CentralView ArticleGoogle Scholar
- Olsson J, Lovheim H, Honkala E, Karhunen PJ, Elgh F, Kok EH. HSV presence in brains of individuals without dementia: the TASTY brain series. Dis Model Mech. 2016;9:1349–55.PubMedPubMed CentralView ArticleGoogle Scholar
- Le Guennec L, Mokhtari K, Chauvet D, Dupuis N, Roos-Weil D, Agut H, Leclercq D, Psimaras D, Mayaux J, Demeret S, et al. Human Herpesvirus 6 (HHV-6) necrotizing encephalitis, a rare condition in immunocompromised patients: the importance of brain biopsy associated with HHV-6 testing. J Neurol Sci. 2017;377:112–5.PubMedView ArticlePubMed CentralGoogle Scholar
- Yoon JY, Danielson B, Mathis D, Karamchandani J, Munoz DG. Cytomegalovirus in the human dentate gyrus and its impact on neural progenitor cells: report of two cases. Clin Neuropathol. 2017;36:240–5.PubMedView ArticlePubMed CentralGoogle Scholar
- Carpenter JE, Clayton AC, Halling KC, Bonthius DJ, Buckingham EM, Jackson W, Dotzler SM, Card JP, Enquist LW, Grose C. Defensive perimeter in the central nervous system: predominance of astrocytes and astrogliosis during recovery from varicella-zoster virus encephalitis. J Virol. 2016;90:379–91.PubMedView ArticleGoogle Scholar
- Dourmashkin RR, McCall SA, Dourmashkin N, Hannah MJ. Virus-like particles and enterovirus antigen found in the brainstem neurons of Parkinson’s disease. F1000Res. 2018;7:302.PubMedPubMed CentralView ArticleGoogle Scholar
- Isumi H, Nunoue T, Nishida A, Takashima S. Fetal brain infection with human parvovirus B19. Pediatr Neurol. 1999;21:661–3.PubMedView ArticleGoogle Scholar
- Reynaud JM, Jegou JF, Welsch JC, Horvat B. Human herpesvirus 6A infection in CD46 transgenic mice: viral persistence in the brain and increased production of proinflammatory chemokines via Toll-like receptor 9. J Virol. 2014;88:5421–36.PubMedPubMed CentralView ArticleGoogle Scholar
- Campbell A, Hogestyn JM, Folts CJ, Lopez B, Proschel C, Mock D, Mayer-Proschel M. Expression of the human herpesvirus 6A latency-associated transcript U94A disrupts human oligodendrocyte progenitor migration. Sci Rep. 2017;7:3978.PubMedPubMed CentralView ArticleGoogle Scholar
- Caselli E, Zatelli MC, Rizzo R, Benedetti S, Martorelli D, Trasforini G, Cassai E, Degli Uberti EC, Luca D, Dolcetti R. Virologic and immunologic evidence supporting an association between HHV-6 and Hashimoto’s thyroiditis. PLoS Pathog. 2012;8:e1002951.PubMedPubMed CentralView ArticleGoogle Scholar
- Sultanova A, Cistjakovs M, Gravelsina S, Chapenko S, Roga S, Cunskis E, Nora-Krukle Z, Groma V, Ventina I, Murovska M. Association of active human herpesvirus-6 (HHV-6) infection with autoimmune thyroid gland diseases. Clin Microbiol Infect. 2017;23(50):e51–5.Google Scholar
- Broccolo F, Fusetti L, Ceccherini-Nelli L. Possible role of human herpesvirus 6 as a trigger of autoimmune disease. Sci World J. 2013;2013:867389.View ArticleGoogle Scholar
- Broccolo F, Drago F, Cassina G, Fava A, Fusetti L, Matteoli B, Ceccherini-Nelli L, Sabbadini MG, Lusso P, Parodi A, Malnati MS. Selective reactivation of human herpesvirus 6 in patients with autoimmune connective tissue diseases. J Med Virol. 2013;85:1925–34.PubMedView ArticleGoogle Scholar
- Soldan SS, Berti R, Salem N, Secchiero P, Flamand L, Calabresi PA, Brennan MB, Maloni HW, McFarland HF, Lin HC, et al. Association of human herpes virus 6 (HHV-6) with multiple sclerosis: increased IgM response to HHV-6 early antigen and detection of serum HHV-6 DNA. Nat Med. 1997;3:1394–7.PubMedView ArticleGoogle Scholar
- Cirone M, Cuomo L, Zompetta C, Ruggieri S, Frati L, Faggioni A, Ragona G. Human herpesvirus 6 and multiple sclerosis: a study of T cell cross-reactivity to viral and myelin basic protein antigens. J Med Virol. 2002;68:268–72.PubMedView ArticleGoogle Scholar
- Niehusmann P, Widman G, Eis-Hubinger AM, Greschus S, Robens BK, Grote A, Becker AJ. Non-paraneoplastic limbic encephalitis and central nervous HHV-6B reactivation: causality or coincidence? Neuropathology. 2016;36:376–80.PubMedView ArticleGoogle Scholar
- Descamps V, Ranger-Rogez S. DRESS syndrome. Joint Bone Spine. 2014;81:15–21.PubMedView ArticleGoogle Scholar
- Shiohara T, Kano Y. Drug reaction with eosinophilia and systemic symptoms (DRESS): incidence, pathogenesis and management. Expert Opin Drug Saf. 2017;16:139–47.PubMedGoogle Scholar
- Mine S, Suzuki K, Sato Y, Fukumoto H, Kataoka M, Inoue N, Ohbayashi C, Hasegawa H, Sata T, Fukayama M, Katano H. Evidence for human herpesvirus-6B infection of regulatory T-cells in acute systemic lymphadenitis in an immunocompetent adult with the drug reaction with eosinophilia and systemic symptoms syndrome: a case report. J Clin Virol. 2014;61:448–52.PubMedView ArticleGoogle Scholar
- Wang F, Chi J, Peng G, Zhou F, Wang J, Li L, Feng D, Xie F, Gu B, Qin J, et al. Development of virus-specific CD4+ and CD8+ regulatory T cells induced by human herpesvirus 6 infection. J Virol. 2014;88:1011–24.PubMedPubMed CentralView ArticleGoogle Scholar
- Wang F, Yao K, Yin QZ, Zhou F, Ding CL, Peng GY, Xu J, Chen Y, Feng DJ, Ma CL, Xu WR. Human herpesvirus-6-specific interleukin 10-producing CD4+ T cells suppress the CD4+ T-cell response in infected individuals. Microbiol Immunol. 2006;50:787–803.PubMedView ArticleGoogle Scholar
- Theorell J, Bileviciute-Ljungar I, Tesi B, Schlums H, Johnsgaard MS, Asadi-Azarbaijani B, Bolle Strand E, Bryceson YT. Unperturbed cytotoxic lymphocyte phenotype and function in myalgic encephalomyelitis/chronic fatigue syndrome patients. Front Immunol. 2017;8:723.PubMedPubMed CentralView ArticleGoogle Scholar
- Ogawa E, Otaguro S, Murata M, Kainuma M, Sawayama Y, Furusyo N, Hayashi J. Intravenous immunoglobulin therapy for severe arthritis associated with human parvovirus B19 infection. J Infect Chemother. 2008;14:377–82.PubMedView ArticleGoogle Scholar
- Cohen BJ, Buckley MM, Clewley JP, Jones VE, Puttick AH, Jacoby RK. Human parvovirus infection in early rheumatoid and inflammatory arthritis. Ann Rheum Dis. 1986;45:832–8.PubMedPubMed CentralView ArticleGoogle Scholar
- Kerr JR, Boyd N. Autoantibodies following parvovirus B19 infection. J Infect. 1996;32:41–7.PubMedView ArticleGoogle Scholar
- Naciute M, Mieliauskaite D, Rugiene R, Maciunaite G, Mauricas M, Murovska M, Girkontaite I. Parvovirus B19 infection modulates the levels of cytokines in the plasma of rheumatoid arthritis patients. Cytokine. 2017;96:41–8.PubMedView ArticleGoogle Scholar
- Hsu TC, Tzang BS, Huang CN, Lee YJ, Liu GY, Chen MC, Tsay GJ. Increased expression and secretion of interleukin-6 in human parvovirus B19 non-structural protein (NS1) transfected COS-7 epithelial cells. Clin Exp Immunol. 2006;144:152–7.PubMedPubMed CentralView ArticleGoogle Scholar
- Fan MM, Tamburic L, Shippam-Brett C, Zagrodney DB, Astell CR. The small 11-kDa protein from B19 parvovirus binds growth factor receptor-binding protein 2 in vitro in a Src homology 3 domain/ligand-dependent manner. Virology. 2001;291:285–91.PubMedView ArticleGoogle Scholar
- Duechting A, Tschope C, Kaiser H, Lamkemeyer T, Tanaka N, Aberle S, Lang F, Torresi J, Kandolf R, Bock CT. Human parvovirus B19 NS1 protein modulates inflammatory signaling by activation of STAT3/PIAS3 in human endothelial cells. J Virol. 2008;82:7942–52.PubMedPubMed CentralView ArticleGoogle Scholar
- Tsay GJ, Zouali M. Unscrambling the role of human parvovirus B19 signaling in systemic autoimmunity. Biochem Pharmacol. 2006;72:1453–9.PubMedView ArticleGoogle Scholar
- Attard L, Bonvicini F, Gelsomino F, Manfredi R, Cascavilla A, Viale P, Varani S, Gallinella G. Paradoxical response to intravenous immunoglobulin in a case of Parvovirus B19-associated chronic fatigue syndrome. J Clin Virol. 2015;62:54–7.PubMedView ArticleGoogle Scholar