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Virus Adaptation and Treatment
open access to scientific and medical research Open Access Full Text Article A paradigm linking herpesvirus immediate-early gene expression apoptosis and myalgic encephalomyelitis chronic fatigue syndrome This article was published in the following Dove Press journal: Virus Adaptation and Treatment21 February 2011Number of times this article has been viewed Abstract: There is no accepted science to relate herpesviruses (Epstein–Barr virus [EBV],
human cytomegalovirus [HCMV], and human herpesvirus 6 [HHV6]) as causes of myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS). ME/CFS patients have elevated 1Department of Medicine, William Beaumont hospital, serum immunoglobulin (Ig)G serum antibody titers to EBV, HCMV, and HHV6, but there royal Oak, Mi, UsA; is no herpesvirus DNA-emia, herpesvirus antigenemia, or uniformly elevated IgM serum 2DcL Medical Laboratories, indianapolis, in, UsA antibody titers to the complete virions. We propose that herpesvirus EBV, HCMV, and HHV6
immediate-early gene expression in ME/CFS patients leads to host cell dysregulation and
host cell apoptosis without lytic herpesvirus replication. Specific antiviral nucleosides, which
alleviate ME/CFS, namely valacyclovir for EBV ME/CFS and valganciclovir for HCMV/
HHV6 ME/CFS, inhibit herpesvirus DNA polymerases and/or thymidine kinase functions, thus
inhibiting lytic virus replication. New host cell recruitment thus ceases. In the absence of new
herpesvirus, nonpermissive herpesvirus replication stops, and ME/CFS recovery ensues.
Keywords: ME/CFS, Epstein–Barr virus (EBV), human cytomegalovirus (HCMV), HHV6,
abortive replication
The gamma herpesvirus Epstein–Barr virus (EBV) and both beta herpesviruses human cytomegalovirus (HCMV) and human herpesvirus 6 (HHV6) have biphasic life-cycles of replication and latency during which these large virus genomes are expanded or maintained, respectively.1 During virus latency, both EBV and HCMV are closed, circular, nonintegrated intranuclear episomes; however, HHV6 is integrated into host cell DNA.2 EBV has a malignant potential and is associated with nasopharyngeal carcinoma, Burkitt's lymphoma, and AIDS-related lymphoproliferative disorder. Previous research has suggested and denied that herpesviruses are associated with myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS).3–6 ME/CFS illness, like herpesviruses, is experienced worldwide, with over one million CFS sufferers in the US alone.5 Canonical evidence for herpesvirus not being the cause of ME/CFS is that there is no herpesvirus DNA-emia, herpesvirus antigenemia, or uniform serum immunoglobulin (Ig)M antibody increase to complete herpesvirus virion or increasing herpesvirus IgG serum antibody titers (Table 1). Nevertheless, we have developed a successful specific serum–cardiac biomarker diagnostic panel for herpesvirus subset- correspondence: A Martin Lerner 32804 Pierce rd, Beverly hills, directed treatment of CFS.6 Using this diagnostic panel, a systemic review of 142 CFS patients completing $6 months of herpesvirus subset-directed antiviral therapy at a Tel +1 248 540 9866 Fax +1 248 540 0139 single treatment center from 2001 to 2007, including over 7000 patient visits and cap- turing over 35,000 fields of information, was analyzed. This study distinguished for submit your manuscript
Virus Adaptation and Treatment 2011:3 19–24 2011 Lerner and Beqaj, publisher and licensee Dove Medical Press Ltd. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.
Table 1 comparative herpesvirus permissive and nonpermissive replication
Result
1. Pathogenic process necrosis of host cell and new infectious virus Apoptosis of host cell, no new infectious virus 2. circulation (blood and lymphatics) eBV (memory B-cell), hcMV (macrophage, monocyte), hhV6 (T-cell) 5. igM antibody to complete virus 6. igM antibody to nonstructural 7. serum igg antibody titer to Yes, no increase in igg titer 8. immediate-early virus gene 9. Activation of late viral gene 10. Therapeutic effect of specific Yes (slow), prevents new host cell eBV, hcMV, hhV6 DnA recruitment (see Figure 1) polymerase inhibitors 11. Proposed therapeutic effect of specific EBV, HCMV, HHV6 inhibitors of immediate-early gene products 12. clinical entities infectious mononucleosis, myocarditis, Me/cFs, retinitis, interstitial pneumonia meningoencephalitis, polyneuropathy, thyroiditis: enteritis, pneumonia, retinitis Abbreviations: cFs, chronic fatigue syndrome; eBV, epstein–Barr virus; hcMV, human cytomegalovirus; hhV6, human herpesvirus 6; ig, immunoglobulin.
the first time two clinically identical ME/CFS groups, which Initially, ME/CFS patients had abnormal 24-h electrocar- we designate group A and group B. Among the 142 ME/CFS diography (ECG) recordings with resting tachycardias and patients, 106 were group A patients and 36 were group B abnormal left ventricular T-wave repolarizations, abnormal patients. Each of the 142 ME/CFS patients had elevated myocardial dynamics, and decreased left ventricular ejection serum IgG antibody titers to EBV, HCMV, and/or HHV6 in fractions.8–10 Accompanying symptoms were a pervasive single or multiple infections. The 106 group A ME/CFS life-altering fatigue, vasodepressive syncope, chest pains, patients had no co-infections, but group B CFS patients had fever, cervical lymphadenopathy, and muscle aches or joint co-infections with tick-borne Borrelia burgdorferi, B abesia pain.3 All of these findings improved or disappeared with microti, or Anaplasma (Ehrlichia) phagocytophila. Adult long-term antiviral nucleosides.6 Resting standard 12-lead rheumatic fever was also an indistinguishable co-infection. ECGs did not detect these cardiac abnormalities, which only After analysis of the 142 ME/CFS patients was completed, became apparent with tachycardia. With antiviral therapy, Mycoplasma pneumoniae was added to possible group B elevated EBV, HCMV, HHV6 herpesvirus serum antibody titers fell.11–15 The mean EIPS of the 106 group A ME/CFS A specific ME/CFS designed and validated Energy Index patients increased from baseline ,4 to final .6.5, with a Point Score (EIPS) monitored severity of ME/CFS illnesses mean duration of antiviral treatment of 2.4 years. A former every 3 months over the 72 months of the study.7 Group A CFS patient (EIPS 4) with an EIPS of 6.5 can now fully ME/CFS patients were treated with long-term valacyclovir participate in activities of normal living.
for EBV ME/CFS subsets, or long-term valganciclovir for Surprisingly, after beginning valacyclovir/valganciclovir, HCMV or HHV6 ME/CFS subsets. ME/CFS patients with the earliest time at which clinical improvement began was both EBV and HCMV/HHV6 subsets were given both 6 months, which is far beyond what might customarily be nucleosides. With the specific diagnostic panel determining expected. We offer a paradigm to explain both the absence antiviral therapy for the ME/CFS group and subset, 79 of the of DNA-emia, antigenemia, and IgM antibody to complete 106 group A ME/CFS patients (74.5%) now continue normal virus and the long-time interval before ME/CFS patients lives (P , 0.0001).6 This is an unprecedented result.
begin recovery.
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Virus Adaptation and Treatment 2011:3 herpesvirus apoptosis and Me/cFs Evidence that in the EBV subset, ME/CFS patients treated patients" and indirectly inhibit nonpermissive virus replica- with long-term elevated EBVEA(D) and/or EBV, VCA tion, thereby facilitating recovery from ME/CFS illness18 IgM serum antibody titers valacyclovir decrease is shown (Table 1, Figure 1).
in Table 2.10 Elevated EBVEA(D) serum antibody titers We propose that ME/CFS patients have nonpermissive in ME/CFS patients 1, 4, and 5 decreased with long-term herpesvirus (EBV, HCMV, HHV6) replication, expressing valacyclovir. Similarly, in ME/CFS patients, 2, 3, and 6 with immediate-early (IE) gene products, which induce host baseline elevated EBV, VCA IgM serum titers decreased. cell dysregulation and host cell apoptosis.19,20 At biopsy Elevated EBV, VCA IgM serum antibody titers are present in ME/CFS patients, cardiac muscle fiber apoptosis is in approximately 15% of EBV subset ME/CFS patients, and present, but EBV and HCMV polymerase chain reactions elevated EBV early antigen (EA)(D) serum titers are regularly for complete virus are negative.21 present in EBV subset patients.14 Simultaneous myocardial The three earliest genes expressed during initiation of dynamic studies of left ventricular ejection fractions showed the EBV lytic cycle are the IE genes zta (BZLF1 and EB1), a co-occurring increase in left ventricular ejection fractions Rta (R and BRLF1), and Mta (SM, BMLF1, and EB2). with a mean value of +10.8 units (+18.9%), P = 0.007. The These early genes and their proteins Z (ZEBA, Zta, EBI) EIPS for these same six EBV ME/CFS patients improved are essential for EBV lytic replication. The EBNA-2 gene from 3.7 to 6.5, P = 0.003. Tachycardias at rest, abnormal is anti-apoptotic, favoring progression of the lytic cycle; oscillating T-wave flattenings and inversions with 24-h ECG therefore, serum assays for this late gene product are not monitoring, and multiple symptoms improved with long-term included in the ME/CFS diagnostic profile.6,14,22 The Zta valacyclovir.10–14 Among the 106 group A ME/CFS patients IE gene product induces apoptosis with activation of many followed for at least 6 months in 2001–2007, there were cellular proteolytic enzymes. Zta binds with high affinity to 42.5% with single herpesvirus EBV, HCMV, or HHV6 subsets cellular AP-1 sites, altering host cell signaling and inducing and 57.5% with multiple herpesvirus ME/CFS.6 Single and IL-6, IL-10, TGFß, the tyrosine kinase TKT, matrix metallo- multiple ME/CFS patients responded equally.
proteinases (MMPI and MMP-9) c-Fos, and the early growth Valacyclovir and valganciclovir inhibit viral EBV, response (EGR-1). IL-10 and TgFß suppress host immune HCMV, or HHV6 replication by inhibiting the core proteins, responses. In infected and uninfected cells, EBV Zta is taken DNA polymerase, and thymidine kinase, which occupy up and directed to the nucleus, activating apoptosis. Zta approximately the 50th gene of the early, middle, and late inhibits IL-10, decreasing macrophage and NK cell functions, sequential cascade of the several hundred herpesvirus genes NK and T-cell mediated cytotoxic responses, MHC class I in each of the three genomes. The murine retrovirus XMRV molecules and immune presentations of lytic viral antigens, may compromise immune function in ME/CFS patients, and major tumor necrosis factor alpha receptor (TNF-R1). facilitating nonpermissive herpesvirus replication.16,17 Zta minimizes responses to TNF-receptor-mediated apop- We suggest that in ME/CFS patients, valacyclovir and tosis signaling interferons. Zta mitigates the innate adaptive valganciclovir inhibit the herpesvirus lytic replication cycle immune responses to EBV reactivation. Zta mediates these and thus prevent "recruitment of new host cells to ME/CFS signaling events without EBV gene progression to the lytic Table 2 Phase ii: valacyclovir treatment in six cFs patients with single-virus eBV infections (eBV antibody titers in serum)
Left ventricular ejection fraction (units)
Viral capsid
Energy index point score
antigen, IgM
Notes: *studies performed after 6 months of valacyclovir treatment. copyright 2002, Drugs Today. reprinted with permission from Lerner AM, Beqaj sh, Deeter hJ,
et al. A six-month trial of valacyclovir in the epstein-Barr virus subset of chronic fatigue syndrome: improvement in left ventricular function. Drugs Today. 2002;38:549–561.
Abbreviations: cFs, chronic fatigue syndrome; eBV, epstein–Barr virus; ig, immunoglobulin.
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Host cell necrosis Apoptosis host cell Non-permissive phase Figure 1 During the proposed three phases of herpesvirus replication (a) host cell and (b) herpesvirus bind at the cytoplasmic membrane (ab) and (c) herpesvirus transits
intranuclearly. Permissive herpesvirus replication yields I) new virus and host cell necrosis infectious mononucleosis; II) the latent herpesvirus phase preserves both the virus
genome and the healthy host cell; III) nonpermissive herpesvirus replication yields host cell apoptosis no new virus and Me/cFs.
Abbreviations: cFs, chronic fatigue syndrome; Me, myalgic encephalomyelitis.
cascade.23–31 ME/CFS illness may require herpesvirus IE gene uniquely elevated serum antibody titers to the nonstructural product-induced apoptosis with associated cellular dysregu- gene products EBV-specific DNase and DNA polymerase. lation and proteolysis without virus lytic cycle completion These elevated EBV-specific serum antibody titers are and new infectious herpesvirus. Herpesvirus nonpermissive also present in patients with EBV-related malignancies, replication may also be a pathogenic mechanism in HCMV Burkitt's lymphoma, and nasopharyngeal carcinoma, but interstitial pneumonia where virus recovery in the lung does are not present in patients with infectious mononucleosis not correlate with virus titers in affected tissues.32–34 or in healthy individuals. The EBV-EA(D) encodes for at In the ME/CFS patient, EBV, HCMV, and HHV6 least six different virus enzymes, including deoxyuridine herpesviruses may enter host cells and initiate IE gene triphosphate nucleotidohydoxylase (dUTPase). This early products, host cell dysregulation, cellular proteolysis, gene product, like HCMV, IE, and IE , induces activation of and inhibition of the immune response and apoptosis. proinflammatory cytokines through NK-K6, demonstrating No infectious new virus results. ME/CFS illness is consistent that EBV dUTPase is a pathogen-associated molecule and with herpesvirus IE gene product nonlytic-induced apoptosis. that it has immunomodulator functions. Direction of anti- Valacyclovir and valganciclovir inhibit new host cell herpes- viral therapy toward inhibition of IE genes of EBV, HCMV, virus recruitment and, ultimately, herpesvirus IE-induced host and HHV6 may well shorten the time for ME/CFS recov- cell apoptosis. ME/CFS clinical recovery follows.6,14 Direct ery using the nucleosides valacyclovir and valganciclovir, anti-ME/CFS therapy may be inhibition of EBV, HCMV, and which inhibit only the DNA polymerases and thymidine HHV6 IE gene expression with drugs such as the antisense kinases of these herpesviruses that are present at a relatively oligonucleotide ISIS 2922.35,36 Kogelnik et al have described mid-gene location in these large genomes.
the therapeutic effect of valganciclovir in ME/CFS patients with HHV6 subset CFS, and Klimas and O'Brien have sum- marized inflammatory immune functions in ME/CFS that are We gratefully appreciate Deanna Mason and Deborah compatible with the host cell dysregulation we propose.37–39 McNeilance, transcriptionists. We recognize and thank Further evidence for IE-induced pathology and Leonard A Jason, Center for Community Research, nonpermissive replication in the EBV subset ME/ DePaul University, Chicago, Illinois, USA; James Edington CFS parallel to that in the HCMV subset ME/CFS (eg, (for Figure 1 and Table 1), Ann Cavanagh, and Ken Gill, of p52 and CM ) is the work of Glaser, Williams, and the Dr A Martin Lerner CFS Foundation, for critical review colleagues.11,12,40–44 EBV ME/CFS subset patients also have of this manuscript.
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Virus Adaptation and Treatment 2011:3 herpesvirus apoptosis and Me/cFs 16. Lombardi VC, Ruscetti FW, Das Gupta J, et al. Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic There was no grant or pharmaceutical support. Drs Lerner fatigue syndrome. Science. 2009;326(5952):585–589.
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Environ. Sci. Technol. 2003, 37, 2400-2409 Fate and Transport of 17â-Estradiol great number of people and wildlife can be impacted byexposure to reproductive hormones, especially since they in Soil-Water Systems can produce adverse effects at remarkably low concentrations(<1.0 ng L-1; 2-4). For example, 17â-estradiol has been foundto cause vitellogenin production in male fish at environmental