ME and CFS Medical Abnormalities – Herpesviruses

 

Following is a list of articles about abnormalities with herpesviruses in ME and CFS.

Links to the more than 1,000 peer-reviewed journal articles are listed on the ME and CFS Medical Abnormalities page of this website.

 

Loebel M, Eckey M, Sotzny F, Hahn E, Bauer S, Grabowski P, Zerweck J, Holenya P, Hanitsch LG, Wittke K, Borchmann P, Rüffer JU, Hiepe F, Ruprecht K, Behrends U, Meindl C, Volk HD, Reimer U, Scheibenbogen C. Serological profiling of the EBV immune response in Chronic Fatigue Syndromeusing a peptide microarray. PLoS One. 2017 Jun 12;12(6):e0179124. PMID: 28604802

Patients with CFS had a quite similar EBV IgG antibody response pattern as healthy controls. Enhanced IgG reactivity against an EBNA-6 repeat sequence and against EBNA-6 protein is found in CFS patients. Homologous sequences of various human proteins with this EBNA-6 repeat sequence might be potential targets for antigenic mimicry.

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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 May;102:8-15. PMID: 28478837

According to the hypothesis presented here, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) develops over 3 steps: Step 1 is characterized by the aggregation of lymphoid cells in dorsal root ganglia or other nervous structures. In step 2, Epstein-Barr virus (EBV)-infected lymphocytes or monocytes bring EBV from the circulation to one or several of these lymphoid aggregates, whereupon cell-to-cell transmission of EBV and proliferation of latently EBV-infected lymphocytes lead to the presence of many EBV-infected cells in the lymphoid aggregates. In step 3, immune cell exhaustion contributes to a consolidation of the pathological processes.

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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 Sep;89(9):1636-1645. PMID: 28303641

The results of this study demonstrate that a significant percentage of patients with ME/CFS and GWI are simultaneously producing antibodies against multiple human herpesviruses-encoded dUTPases and/or the human dUTPase when compared to controls. GWI patients exhibited significantly higher levels of antibodies to the HHV-6 and human dUTPases than controls, while the ME/CFS cohort had higher anti-EBV-dUTPase antibodies than in both GWI patients and controls, as well as significantly higher anti-human dUTPase antibodies than in controls

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Williams MV, Cox B, Ariza ME. Herpesviruses dUTPases: A New Family of Pathogen-Associated Molecular Pattern (PAMP) Proteins with Implications for Human Disease. Pathogens. 2016 Dec 28;6(1). PMID: 28036046

In this review, we provide evidence from animal and human studies of the Epstein-Barr virus as a prototype, supporting the notion that herpesviruses dUTPases are a family of proteins with unique immunoregulatory functions that can alter the inflammatory microenvironment and thus exacerbate the immune pathology of herpesvirus-related diseases including myalgic encephalomyelitis/chronic fatigue syndrome, autoimmune diseases, and cancer.

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Aoki R, Kobayashi N, Suzuki G, Kuratsune H, Shimada K, Oka N, Takahashi M, Yamadera W, Iwashita M, Tokuno S, Nibuya M, Tanichi M, Mukai Y, Mitani K, Kondo K, Ito H, Nakayama K. Human herpesvirus 6 and 7 are biomarkers for fatigue, which distinguish between physiological fatigue and pathological fatigue. Biochem Biophys Res Commun. 2016 Sep 9;478(1):424-430. PMID: 27396623

The authors report on the measurement of salivary human herpesvirus (HHV-) 6 and HHV-7 as biomarkers for quantifying physiological fatigue. However, HHV-6 and HHV-7 did not increase in obstructive sleep apnea syndrome (OSAS), chronic fatigue syndrome (CFS) and major depressive disorder (MDD), which are thought to cause pathological fatigue.

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Harvey JM, Broderick G, Bowie A, Barnes ZM, Katz BZ, O’Gorman MRG, Vernon SD, Fletcher MA, Klimas NG, Taylor R. Tracking post-infectious fatigue in clinic using routine Lab tests. BMC Pediatr. 2016 Apr 26;16:54. PMID: 27118537

Lower ACTH levels at 6 months post infectious mononucleosis (IM) diagnosis in adolescents were highly predictive of CFS. ACTH levels in CFS overlapped with healthy controls at 12 months, but again showed a trend towards a deficiency at 24 months. Conversely, estradiol levels depart significantly from normal at 12 months only to recover at 24 months. Finally, relative neutrophil count showed a significant departure from normal at 24 months in CFS. Expression of these markers evolved differently over time between groups.

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Lum E, Medveczky MM, Medveczky PG. Is inherited human herpesvirus 6 the perpetrator behind some cases of chronic fatigue syndrome? Future Microbiol. 2014;9(4):433-6. PMID: 24810341

The authors discuss the possible role of HHV6 in CFS.

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Jason LA, Katz BZ, Shiraishi Y, Mears CJ, Im Y, Taylor R. Predictors of Post-Infectious Chronic Fatigue Syndrome in Adolescents. Health Psychol Behav Med. 2014 Jan 1;2(1):41-51. PMID: 24660116

This study focused on identifying risk factors for the acquisition of CFS in adolescents following Infectious Mononucleosis. A number of variables were predictors of post-infectious CFS at 6 months; however, when autonomic symptoms were used as a control variable, only days spent in bed since mono was a significant predictor.

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Loebel M, Strohschein K, Giannini C, Koelsch U, Bauer S, Doebis C, Thomas S, Unterwalder N, von Baehr V, Reinke P, Knops M, Hanitsch LG, Meisel C, Volk HD, Scheibenbogen C. Deficient EBV-specific B- and T-cell response in patients with chronic fatigue syndrome. PLoS One. 2014 Jan 15;9(1):e85387. PMID: 24454857

The authors analyzed the EBV-specific memory B- and T-cell response in patients with CFS. While they observed no difference in viral capsid antigen (VCA)-IgG antibodies, EBV nuclear antigen (EBNA)-IgG titers were low or absent in 10% of CFS patients. When analyzing the EBV-specific memory B-cell reservoir in vitro a diminished or absent number of EBNA-1- and VCA-antibody secreting cells was found in up to 76% of patients. They proposed a deficient EBV-specific B- and T-cell memory response in CFS patients and suggest an impaired ability to control early steps of EBV reactivation.

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Tsai SY, Yang TY, Chen HJ, Chen CS, Lin WM, Shen WC, Kuo CN, Kao CH. Increased risk of chronic fatigue syndrome following herpes zoster: a population-based study. Eur J Clin Microbiol Infect Dis. 2014 Apr 9. PMID: 24715153

Researchers in Taiwan identified more than 9,000 patients with herpes zoster (HZ) infection and 36,000 patients without herpes zoster infections. The incidence rate of CFS was higher in the HZ cohort than in the non-HZ cohort.

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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 May;56(10):1394-400. PMID:23408682

The authors fail to demonstrate a difference in HERV-K18 env transcripts, HHV-6 viral copy number, and HHV-7 viral copy number between CFS patients and healthy controls.

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Burbelo PD, Bayat A, Wagner J, Nutman TB, Baraniuk JN, Iadarola MJ. No serological evidence for a role of HHV-6 infection in chronic fatigue syndrome. Am J Transl Res. 2012;4(4):443-51. PMID: 23145212

No statistically significant differences in antibody levels or frequency of HHV-6A or HHV-6B infection were detected between the controls and CFS patients.

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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. PMID: 22927850

Active viral infection with HHV6, HHV7 and/or parvovirus B19 was found in 64.8% of patients and in 13.3% of practically healthy persons. Increase in peripheral blood leukocyte DNA HHV-6 load as well as in proinflammatory cytokines’ levels was detected in patients during active viral infection.

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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(11):e47891. PMID: 23155374

There is prolonged elevated antibody level against the encoded proteins EBV dUTPase and EBV DNA polymerase in a subset of CFS patients.

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Katz BZ, Stewart JM, Shiraishi Y, Mears CJ, Taylor R. Orthostatic tolerance testing in a prospective cohort of adolescents with chronic fatigue syndrome and recovered controls following infectious mononucleosis. Clin Pediatr (Phila). 2012 Sep;51(9):835-9. PMID:22850676

This study suggests that adolescents who meet criteria for CFS 6 months following infectious mononucleosis do not have, as a group, more standing orthostatic intolerance than recovered controls.

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Shapiro JS. Does varicella-zoster virus infection of the peripheral ganglia cause Chronic Fatigue Syndrome? Med Hypotheses. 2009 Nov;73(5):728-34. PMID: 19520522

This article posits that infection of the peripheral ganglia causes at least some cases of Chronic Fatigue Syndrome (CFS), with a neurotropic herpesvirus, particularly varicella-zoster virus (VZV), as the most likely cause of the infection.

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Beqaj SH, Lerner AM, Fitzgerald JT. Immunoassay with cytomegalovirus early antigens from gene products p52 and CM2 (UL44 and UL57) detects active infection in patients with chronic fatigue syndrome. J Clin Pathol. 2008 May;61(5):623-6. PMID: 18037660

Immunoassays that use early antigen recombinant HCMV CM(2) and p52 are five times more sensitive than HCMV ELISA assay using viral lysate, and are specific in the detection and differentiation of active human cytomegalovirus infection in a subset of patients with CFS.

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Bellmann-Weiler R, Schroecksnadel K, Holzer C, Larcher C, Fuchs D, Weiss G. IFN-gamma mediated pathways in patients with fatigue and chronic active Epstein Barr virus-infection. J Affect Disord. 2008 May;108(1-2):171-6. PMID: 17945348

EBV viremia in CFS is associated with cell-mediated immune activation and increased tryptophan degradation.

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Kondo K. Chronic fatigue syndrome and herpesvirus reactivation. Nihon Rinsho. 2007 Jun;65(6):1043-8. PMID: 17561695

The amount of HHV-6 and HHV-7 reactivation has potential as a biomarker for CFS.

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Komaroff AL, Jacobson S, Ablashi DV, Yamanishi K. Highlights from 5th International Conference on HHV-6 and -7. Herpes. 2006 Nov;13(3):81-2. PMID: 17147913

HHV-6 enhances the progression of simian immunodeficiency virus in monkeys.

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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 Dec;37 Suppl 1:S47-51. PMID: 17276369

Reactivation of HHV6 and HHV7 in combination is frequent in CFS patients.

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Komaroff AL. Is human herpesvirus-6 a trigger for chronic fatigue syndrome? J Clin Virol. 2006 Dec;37 Suppl 1:S39-46. PMID: 17276367

HHV6 is common in CFS and may serve to trigger and perpetuate the disease.

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Kondo K. Human herpesvirus latency and fatigue. Uirusu. 2005 Jun;55(1):9-17. PMID:16308525

HHV-6 established latency in the macrophage, kept a fairly stable intermediate stage between latency and reactivation, and the viral reactivation was induced by two or more factors. HHV-6 is reactivated during work-induced fatigue, and HHV-6 reactivation can be an objective biomarker for fatigue.

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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 Mar-Apr;18(2):101-6. PMID: 15113035

Serum antibody to EBV VCA IgM may be a specific diagnostic test for a subset of CFS patients.

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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 May-Jun;16(3):153-9. PMID: 12182109

The study suggests a relationship between CFS and human cytomegalovirus.

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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 Sep 1;35(5):518-25. PMID: 12173124

Identical twins discordant for CFS did not show differences on PCR assays for viral DNA for HHV-6, HHV-7, HHV-8, cytomegalovirus, Epstein-Barr virus, herpes simplex virus, varicella zoster virus, JC virus, BK virus, or parvovirus B19.

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Krueger GR, Koch B, Hoffmann A, Rojo J, Brandt ME, Wang G, Buja LM. Dynamics of chronic active herpesvirus-6 infection in patients with chronic fatigue syndrome: data acquisition for computer modeling. In Vivo. 2001 Nov-Dec;15(6):461-5. PMID: 11887330

Persistent low-dose stimulation by HHV-6 may favor imbalanced immune response rather than overt immune deficiency.

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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 Jul;31(1):48-52. PMID: 10913395

The authors found no evidence that active or latent infection with HHV-6A, HHV-6B, HHV-7, or any combination these 3 HHVs is associated with chronic fatigue syndrome.

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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 May;16(3):179-91. PMID: 10738137

In both MS and CFS patients, the authors found increased levels of HHV-6 antibody and HHV-6 DNA. A decrease in cellular immune responses was also detected in CFS patients.

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Wallace HL 2nd, Natelson B, Gause W, Hay J. Human herpesviruses in chronic fatigue syndrome. Clin Diagn Lab Immunol. 1999 Mar;6(2):216-23. PMID: 10066657

Serological analyses of serum anti-EBV and anti-HHV6 antibody titers showed no significant differences between the CFS and control patients.

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Cuende JI, Civeira P, Diez N, Prieto J. High prevalence without reactivation of herpes virus 6 in subjects with chronic fatigue syndrome. An Med Interna. 1997 Sep;14(9):441-4.  PMID: 9453750

The study showed a high proportion of CFS patients infected with HHV-6 but with low viral load.

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Buchwald D, Ashley RL, Pearlman T, Kith P, Komaroff AL. Viral serologies in patients with chronic fatigue and chronic fatigue syndrome. Med Virol. 1996 Sep;50(1):25-30. PMID: 8890037

Differences in the seroprevalence or GMTs of antibodies to 13 viruses were not consistently found in those with chronic fatigue compared with control subjects, or in any subsets of patients including those with CFS, an acute onset of illness, or a documented fever.

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Schmaling KB, Jones JF. MMPI profiles of patients with chronic fatigue syndrome. J Psychosom Res. 1996 Jan;40(1):67-74. PMID: 8730646

EBV titers were higher among CFS patients and were associated with being more symptomatic.

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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 Nov;172(5):1364-7. PMID: 7594679

More CFS patients than controls had elevated levels of HHV-6 EA-specific IgM, perhaps indicating active replication of HHV-6 in CFS.

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Swanink CM, van der Meer JW, Vercoulen JH, Bleijenberg G, Fennis JF, Galama JM. Epstein-Barr virus (EBV) and the chronic fatigue syndrome: normal virus load in blood and normal immunologic reactivity in the EBV regression assay. Clin Infect Dis. 1995 May;20(5):1390-2. PMID: 7620030

The authors failed to demonstrate a role for reactivation of EBV in CFS.

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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 Jun;33(6):1660-61. PMID: 7650209

HHV-7 was present in over 80% of CFS patients and healthy controls, while the prevalence of HHV-6 variant A increased significantly in CFS cases (22 versus 4%; P = 0.05).

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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(5):269-73. PMID: 8724857

The results suggest that CFS patients may have reactivations of EBV, HHV-6 and HHV-7.

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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 Sep;19(3):448-53. PMID: 7811864

In the majority of cases of CFS, elevation of viral antibody titers does not seem to be due to a nonspecificpolyclonal immune response.

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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(7):587-90. PMID: 7968694

The results suggest active replication of HHV-6 in patients with CFS.

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Natelson BH, Ye N, Moul DE, Jenkins FJ, Oren DA, Tapp WN, Cheng YC. High titers of anti-Epstein-Barr virus DNA polymerase are found in patients with severe fatiguing illness. J Med Virol. 1994 Jan;42(1):42-6. PMID: 8308519

Antibodies against EBV DNAP may be a useful marker in delineating a subset of patients with severe fatiguing illness.

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Wray BB, Gaughf C, Chandler FW Jr, Berry SS, Latham JE, Wood L, DuRant RH. Detection of Epstein-Barr virus and cytomegalovirus in patients with chronic fatigue. Ann Allergy. 1993 Sep;71(3):223-6. PMID: 8396863

Epstein-Barr virus-DNA was detected more frequently in male CFS patients, 5/9 (55.6%), than controls, 0/6 (0%), but there was no difference in frequency in female patients, 4/32 (12.5%), than control subjects, 1/29 (3.4%). Cytomegalovirus-DNA was detected infrequently in patients and controls, 13% versus 22% respectively. The presence of EBV-DNA did not correlate with antibody titers nor with the complaint of sore throat.

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Bond PA. A role for herpes simplex virus in the aetiology of chronic fatigue syndrome and related disorders. Med Hypotheses. 1993 May;40(5):301-8. PMID: 8394501

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Lusso P, Malnati MS, Garzino-Demo A, Crowley RW, Long EO, Gallo RC. Infection of natural killer cells by human herpesvirus 6. Nature. 1993 Apr 1;362(6419):458-62. PMID: 7681936

Herpesvirus can directly target and kill NK cells, a potential strategy to suppress the natural anti-viral immunity of the host.

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Kawai K, Kawai A. Studies on the relationship between chronic fatigue syndrome and Epstein-Barr virus in Japan. Intern Med. 1992 Mar;31(3):313-8. PMID: 1319246

Results of the study suggest that a relationship exists between CFS and EBV.

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Woodward CG, Cox RA. Epstein-Barr virus serology in the chronic fatigue syndrome. J Infect. 1992 Mar;24(2):133-9. PMID: 1314860

CFS patients who displayed elevated titres of antibodies to Early Antigens of EBV did not differ clinically from those displaying titres in the control range. Four of nine patients who had increased antibodies to Early Antigens also had evidence of active enterovirus infection.

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Nishikai M. Chronic fatigue syndrome–study of 51 cases treated at the Second Tokyo National Hospital. Nihon Rinsho. 1992 Nov;50(11):2641-7. PMID: 1337560

In a group of CFS patients, IgG antibody titers to EB virus viral capsid antigen were more elevated in the CFS patient group compared to that of the control, and the mean number of NK cells was lower.

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Josephs SF, Henry B, Balachandran N, Strayer D, Peterson D, Komaroff AL, Ablashi DV HHV-6 reactivation in chronic fatigue syndrome. Lancet. 1991 Jun 1;337(8753):1346-7. PMID: 1674318

HHV-6 is reported to be reactivated in CFS.

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Bertram G, Dreiner N, Krueger GR, Ramon A, Ablashi DV, Salahuddin SZ, Balachandram N. Frequent double infection with Epstein-Barr virus and human herpesvirus-6 in patients with acute infectious mononucleosis. In Vivo. 1991 May-Jun;5(3):271-9. PMID: 1654150

CFS is associated with reactivated HHV-6 and Epstein Barr Virus.

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Jones JF, Streib J, Baker S, Herberger M. Chronic fatigue syndrome: I. Epstein-Barr virus immune response and molecular epidemiology. J Med Virol. 1991 Mar;33(3):151-8. PMID: 1679118

The study analyzed spontaneous transformation rates of peripheral blood lymphocytes, EBV viral genome characteristics as determined by DNA restriction fragment polymorphisms, and antibody production by Western blot analysis. Thirty percent of CFS patients versus 8% of control subjects underwent spontaneous transformation in the two studies. Western blot studies suggested that ill subjects made antibodies to lytic proteins more frequently than did healthy control subjects.

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Buchwald D, Freedman AS, Ablashi DV, Sullivan JL, Caligiuri M, Weinberg DS, Hall CG, Ashley RL, Saxinger C, Balachandran N, et al. A chronic “postinfectious” fatigue syndrome associated with benign lymphoproliferation, B-cell proliferation, and active replication of human herpesvirus-6. J Clin Immunol. 1990 Nov;10(6):335-44. PMID: 1964694

A patient with ME and HHV6 is profiled.

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Gold D, Bowden R, Sixbey J, Riggs R, Katon WJ, Ashley R, Obrigewitch RM, Corey L. Chronic fatigue. A prospective clinical and virologic study. JAMA. 1990 Jul 4;264(1):48-53. PMID: 2162397

No evidence of ongoing EBV infection with either transforming or nontransforming strains was demonstrated in this population of CFS patients.

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Jones JF, Williams M, Schooley RT, Robinson C, Glaser R. Antibodies to Epstein-Barr virus-specific DNase and DNA polymerase in the chronic fatigue syndrome. Arch Intern Med. 1988 Sep;148(9):1957-60. PMID: 2843138

Antibodies acting against EBV-specific DNase and DNA polymerase, which are expressed only during virus replication, were assayed. Three of the six patients with elevated anti-EBV enzyme antibody levels developed fatal lymphomas.

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Ablashi DV, Josephs SF, Buchbinder A, Hellman K, Nakamura S, Llana T, Lusso P, Kaplan M, Dahlberg J, Memon S, et al. Human B-lymphotropic virus (human herpesvirus-6). J Virol Methods. 1988 Sep;21(1-4):29-48. PMID: 2846617

Human B-lymphotropic virus (HBLV), also known as human herpesvirus-6 (HHV-6), is elevated in AIDS patients and patients with chronic fatigue syndrome.

 

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