Category: Viruses

No serological evidence for a role of HHV-6 infection in chronic fatigue syndrome

Abstract:

Human herpesvirus 6A (HHV-6A) and human herpesvirus 6B (HHV-6B) are associated with a variety of conditions including rash, fever, and encephalitis and may play a role in several neurological diseases. Here luciferase immunoprecipitation systems (LIPS) was used to develop HHV-6 serologic diagnostic tests using antigens encoded by the U11 gene from HHV-6A (p100) and HHV-6B (p101).

Analysis of the antibody responses against Renilla luciferase fusions with different HHV-6B p101 fragments identified an antigenic fragment (amino acids 389 to 858) that demonstrated ~86% seropositivity in serum samples from healthy US blood donors. Additional experiments detected a HHV-6A antigenic fragment (amino acids 751-870) that showed ~48% antibody seropositivity in samples from Mali, Africa, a known HHV-6A endemic region. In contrast to the high levels of HHV-6A immunoreactivity seen in the African samples, testing of US blood donors with the HHV-6A p100 antigenic fragment revealed little immunoreactivity.

To potentially explore the role of HHV-6 infection in human disease, a blinded cohort of controls (n=59) and chronic fatigue syndrome (CFS) patients (n=72) from the US was examined for serum antibodies. While only a few of the controls and CFS patients showed high level immunoreactivity with HHV-6A, a majority of both the controls and CFS patients showed significant immunoreactivity with HHV-6B. However, no statistically significant differences in antibody levels or frequency of HHV-6A or HHV-6B infection were detected between the controls and CFS patients. These findings highlight the utility of LIPS for exploring the seroepidemiology of HHV-6A and HHV-6B infection, but suggest that these viruses are unlikely to play a role in the pathogenesis of CFS.

 

Source: 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. Epub 2012 Oct 10. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3493030/ (Full article)

 

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

Abstract:

The disabling disorder known as chronic fatigue syndrome or myalgic encephalomyelitis (CFS/ME) has been linked in two independent studies to infection with xenotropic murine leukemia virus-related virus (XMRV) and polytropic murine leukemia virus (pMLV). Although the associations were not confirmed in subsequent studies by other investigators, patients continue to question the consensus of the scientific community in rejecting the validity of the association. Here we report blinded analysis of peripheral blood from a rigorously characterized, geographically diverse population of 147 patients with CFS/ME and 146 healthy subjects by the investigators describing the original association. This analysis reveals no evidence of either XMRV or pMLV infection. I

MPORTANCE Chronic fatigue syndrome/myalgic encephalomyelitis has an estimated prevalence of 42/10,000 in the United States, with annual direct medical costs of $7 billion. Here, the original investigators who found XMRV and pMLV (polytropic murine leukemia virus) in blood of subjects with this disorder report that this association is not confirmed in a blinded analysis of samples from rigorously characterized subjects. The increasing frequency with which molecular methods are used for pathogen discovery poses new challenges to public health and support of science. It is imperative that strategies be developed to rapidly and coherently address discoveries so that they can be carried forward for translation to clinical medicine or abandoned to focus resource investment more productively. Our study provides a paradigm for pathogen discovery that may be helpful to others working in this field.

 

Source: Alter HJ, Mikovits JA, Switzer WM, Ruscetti FW, Lo SC, Klimas N, Komaroff AL, Montoya JG, Bateman L, Levine S, Peterson D, Levin B, Hanson MR, Genfi A, Bhat M, Zheng H, Wang R, Li B, Hung GC, Lee LL, Sameroff S, Heneine W, Coffin J, Hornig M, Lipkin WI. 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 Sep 18;3(5). pii: e00266-12. doi: 10.1128/mBio.00266-12. Print 2012. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3448165/ (Full article)

 

Association of active human herpesvirus-6, -7 and parvovirus b19 infection with clinical outcomes in patients with myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Frequency of active human herpesvirus-6, -7 (HHV-6, HHV-7) and parvovirus B19 (B19) infection/coinfection and its association with clinical course of ME/CFS was evaluated. 108 ME/CFS patients and 90 practically healthy persons were enrolled in the study. Viral genomic sequences were detected by PCR, virus-specific antibodies and cytokine levels-by ELISA, HHV-6 variants-by restriction analysis.

Active viral infection including concurrent infection was found in 64.8% (70/108) of patients and in 13.3% (12/90) 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. Definite relationship was observed between active betaherpesvirus infection and subfebrility, lymphadenopathy and malaise after exertion, and between active B19 infection and multijoint pain. Neuropsychological disturbances were detected in all patients. The manifestation of symptoms was of more frequent occurrence in patients with concurrent infection.

The high rate of active HHV-6, HHV-7 and B19 infection/coinfection with the simultaneous increase in plasma proinflammatory cytokines’ level as well as the association between active viral infection and distinctive types of clinical symptoms shows necessity of simultaneous study of these viral infections for identification of possible subsets of ME/CFS.

 

Source: 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. doi: 10.1155/2012/205085. Epub 2012 Aug 13. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3426163/ (Full article)

 

Loss of stress response as a consequence of viral infection: implications for disease and therapy

Abstract:

Herein, we propose that viral infection can induce a deficient cell stress response and thereby impairs stress tolerance and makes tissues vulnerable to damage. Having a valid paradigm to address the pathological impacts of viral infections could lead to effective new therapies for diseases that have previously been unresponsive to intervention. Host response to viral infections can also lead to autoimmune diseases like type 1 diabetes. In the case of Newcastle disease virus, the effects of viral infection on heat shock proteins may be leveraged as a therapy for cancer. Finally, the search for a specific virus being responsible for a condition like chronic fatigue syndrome may not be worthwhile if the disease is simply a nonspecific response to viral infection.

 

Source: Hooper PL, Hightower LE, Hooper PL. Loss of stress response as a consequence of viral infection: implications for disease and therapy. Cell Stress Chaperones. 2012 Nov;17(6):647-55. doi: 10.1007/s12192-012-0352-4. Epub 2012 Jul 14. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3468676/ (Full article)

 

Retraction for Lo et al., Detection of MLV-related virus gene sequences in blood of patients with chronic fatigue syndrome and healthy blood donors

MEDICAL SCIENCES Retraction for “Detection of MLV-related virus gene sequences in blood of patients with chronic fatigue syndrome and healthy blood donors,” by Shyh-Ching Lo, Natalia Pripuzova, Bingjie Li, Anthony L. Komaroff, Guo-Chiuan Hung, Richard Wang, and Harvey J. Alter, which appeared in issue 36, September 7, 2010, of Proc Natl Acad Sci USA (107:15874–15879; first published August 23, 2010; 10.1073/pnas.1006901107).

Retraction of: Detection of MLV-related virus gene sequences in blood of patients with chronic fatigue syndrome and healthy blood donors. [Proc Natl Acad Sci U S A. 2010]

 

Source: Lo SC, Pripuzova N, Li B, Komaroff AL, Hung GC, Wang R, Alter HJ. Retraction for Lo et al., Detection of MLV-related virus gene sequences in blood of patients with chronic fatigue syndrome and healthy blood donors. Proc Natl Acad Sci U S A. 2012 Jan 3;109(1):346. doi: 10.1073/pnas.1119641109. Epub 2011 Dec 27. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3252929/ (Full article)

 

Failure to confirm XMRV/MLVs in the blood of patients with chronic fatigue syndrome: a multi-laboratory study

Abstract:

Murine leukemia viruses (MLVs), including xenotropic-MLV-related virus (XMRV), have been controversially linked to chronic fatigue syndrome (CFS). To explore this issue in greater depth, we compiled coded replicate samples of blood from 15 subjects previously reported to be XMRV/MLV-positive (14 with CFS) and from 15 healthy donors previously determined to be negative for the viruses. These samples were distributed in a blinded fashion to nine laboratories, which performed assays designed to detect XMRV/MLV nucleic acid, virus replication, and antibody. Only two laboratories reported evidence of XMRV/MLVs; however, replicate sample results showed disagreement, and reactivity was similar among CFS subjects and negative controls. These results indicate that current assays do not reproducibly detect XMRV/MLV in blood samples and that blood donor screening is not warranted.

 

Source: Simmons G, Glynn SA, Komaroff AL, Mikovits JA, Tobler LH, Hackett J Jr, Tang N, Switzer WM, Heneine W, Hewlett IK, Zhao J, Lo SC, Alter HJ, Linnen JM, Gao K, Coffin JM, Kearney MF, Ruscetti FW, Pfost MA, Bethel J, Kleinman S, Holmberg JA, Busch MP; Blood XMRV Scientific Research Working Group (SRWG). Failure to confirm XMRV/MLVs in the blood of patients with chronic fatigue syndrome: a multi-laboratory study. Science. 2011 Nov 11;334(6057):814-7. doi: 10.1126/science.1213841. Epub 2011 Sep 22. Collaborators (25) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3299483/ (Full article)

 

No detectable XMRV in subjects with chronic fatigue syndrome from Quebec

Abstract:

We investigated the presence of XMRV in a cohort of Quebec patients with chronic fatigue syndrome (CFS). DNA was purified from activated peripheral blood mononuclear cells (PBMCs) and PCR was used to detect XMRV gag and env in 72 patients. Anti-XMRV antibodies were searched in sera of 62 patients by Western blot analysis. Attempts to detect XMRV antigens was made, using immunofluorescence with Gag anti-p30 antiserum on activated PBMC from 50 patients. Plasma viremia was measured by RT-PCR on 9 subjects. Finally, detection of infectious virus in 113 CFS subjects was made by co-culture of PHA+IL-2 activated PBMC with human LNCaP carcinoma cells, and by infecting the same susceptible cells with plasma, using a reverse transcriptase (RT) assay as a readout in both experiments. No detection of XMRV footprints nor infectious virus was detected with any of the approaches, in any of the tested individuals.

Copyright © 2011 Elsevier Inc. All rights reserved.

 

Source: Cool M, Bouchard N, Massé G, Laganière B, Dumont A, Hanna Z, Phaneuf D, Morisset R, Jolicoeur P. No detectable XMRV in subjects with chronic fatigue syndrome from Quebec. Virology. 2011 Nov 10;420(1):66-72. doi: 10.1016/j.virol.2011.08.018. Epub 2011 Sep 16. https://www.ncbi.nlm.nih.gov/pubmed/21925693

 

Xenotropic murine leukemia virus-related virus in monozygotic twins discordant for chronic fatigue syndrome

Abstract:

A recent report suggested an association between xenotropic murine leukemia virus-related virus (XMRV) and chronic fatigue syndrome (CFS). If confirmed, this would suggest that antiretroviral therapy might benefit patients suffering from CFS. We validated a set of assays for XMRV and evaluated the prevalence of XMRV in a cohort of monozygotic twins discordant for CFS. Stored peripheral blood mononuclear cell (PBMC) samples were tested with 3 separate polymerase chain reaction (PCR) assays (one of which was nested) for XMRV DNA, and serum/plasma was tested for XMRV RNA by reverse transcription (RT)-PCR. None of the PBMC samples from the twins with CFS or their unaffected co-twins was positive for XMRV, by any of the assays. One plasma sample, from an unaffected co-twin, was reproducibly positive by RT-PCR. However, serum from the same day was negative, as was a follow-up plasma sample obtained 2 days after the positive specimen. These data do not support an association of XMRV with CFS.

Copyright © 2011 Elsevier Inc. All rights reserved.

 

Source: Jerome KR, Diem K, Huang ML, Selke S, Corey L, Buchwald D.Xenotropic murine leukemia virus-related virus in monozygotic twins discordant for chronic fatigue syndrome. Diagn Microbiol Infect Dis. 2011 Sep;71(1):66-71. doi: 10.1016/j.diagmicrobio.2011.06.003. Epub 2011 Jul 26. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3158821/ (Full article)

 

Chronic fatigue syndrome, the immune system and viral infection

Abstract:

The chronic fatigue syndrome (CFS), as defined by recent criteria, is a heterogeneous disorder with a common set of symptoms that often either follows a viral infection or a period of stress. Despite many years of intense investigation there is little consensus on the presence, nature and degree of immune dysfunction in this condition.

However, slightly increased parameters of inflammation and pro-inflammatory cytokines such as interleukin (IL) 1, IL6 and tumour necrosis factor (TNF) α are likely present. Additionally, impaired natural killer cell function appears evident. Alterations in T cell numbers have been described by some and not others.

While the prevalence of positive serology for the common herpes viruses appears no different from healthy controls, there is some evidence of viral persistence and inadequate containment of viral replication. The ability of certain herpes viruses to impair the development of T cell memory may explain this viral persistence and the continuation of symptoms. New therapies based on this understanding are more likely to produce benefit than current methods.

Copyright © 2011 Elsevier Inc. All rights reserved.

 

Source: Bansal AS, Bradley AS, Bishop KN, Kiani-Alikhan S, Ford B. Chronic fatigue syndrome, the immune system and viral infection. Brain Behav Immun. 2012 Jan;26(1):24-31. doi: 10.1016/j.bbi.2011.06.016. Epub 2011 Jul 2. https://www.ncbi.nlm.nih.gov/pubmed/21756995

 

No evidence of murine-like gammaretroviruses in CFS patients previously identified as XMRV-infected

Abstract:

Members of the gammaretroviruses–such as murine leukemia viruses (MLVs), most notably XMRV [xenotropic murine leukemia virus (X-MLV)-related virus–have been reported to be present in the blood of patients with chronic fatigue syndrome (CFS).

We evaluated blood samples from 61 patients with CFS from a single clinical practice, 43 of whom had previously been identified as XMRV-positive. Our analysis included polymerase chain reaction and reverse transcription polymerase chain reaction procedures for detection of viral nucleic acids and assays for detection of infectious virus and virus-specific antibodies.

We found no evidence of XMRV or other MLVs in these blood samples. In addition, we found that these gammaretroviruses were strongly (X-MLV) or partially (XMRV) susceptible to inactivation by sera from CFS patients and healthy controls, which suggested that establishment of a successful MLV infection in humans would be unlikely. Consistent with previous reports, we detected MLV sequences in commercial laboratory reagents. Our results indicate that previous evidence linking XMRV and MLVs to CFS is likely attributable to laboratory contamination.

Comment in: Prostate cancer: XMRV–contaminant, not cause? [Nat Rev Urol. 2011]

 

Source: Knox K, Carrigan D, Simmons G, Teque F, Zhou Y, Hackett J Jr, Qiu X, Luk KC, Schochetman G, Knox A, Kogelnik AM, Levy JA. No evidence of murine-like gammaretroviruses in CFS patients previously identified as XMRV-infected. Science. 2011 Jul 1;333(6038):94-7. doi: 10.1126/science.1204963. Epub 2011 May 31. https://www.ncbi.nlm.nih.gov/pubmed/21628393