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Am J Transl Res 2012;4(4):443-451
Original Article
No serological evidence for a role of HHV-6 infection in chronic fatigue
syndrome
Peter D Burbelo*, Ahmad Bayat*, Jason Wagner, Thomas B Nutman, James N Baraniuk, Michael J Iadarola
Neurobiology and Pain Therapeutics Section, Laboratory of Sensory Biology, National Institute of Dental and
Craniofacial Research, National Institutes of Health, Bethesda, MD; The Laboratory of Parasitic Diseases,
National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; Division
of Rheumatology, Immunology and Allergy, Georgetown University, Washington, D.C. 20007-2197. *Contributed
equally to this study.
Received August 29, 2012; accepted September 25, 2012; Epub October 10, 2012; Published October 30, 2012
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. (AJTR1208006).
Keywords: Chronic Fatigue Syndrome (CFS), Human Herpes Virus-6 (HHV6), luciferase immunoprecipitation
systems (LIPS)
Address all correspondence to:
Dr. James Baraniuk, Division of Rheumatology, Immunology and Allergy, Room 3004F, 3rd Floor, PHC Building,
Georgetown University, 3800 Reservoir road, NW, Washington, D.C. 20007-2197. Tel (202)-687-8231; Fax
(202)-687-9886; E-mail: baraniuj@georgetown.edu
Original Article
No serological evidence for a role of HHV-6 infection in chronic fatigue
syndrome
Peter D Burbelo*, Ahmad Bayat*, Jason Wagner, Thomas B Nutman, James N Baraniuk, Michael J Iadarola
Neurobiology and Pain Therapeutics Section, Laboratory of Sensory Biology, National Institute of Dental and
Craniofacial Research, National Institutes of Health, Bethesda, MD; The Laboratory of Parasitic Diseases,
National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; Division
of Rheumatology, Immunology and Allergy, Georgetown University, Washington, D.C. 20007-2197. *Contributed
equally to this study.
Received August 29, 2012; accepted September 25, 2012; Epub October 10, 2012; Published October 30, 2012
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. (AJTR1208006).
Keywords: Chronic Fatigue Syndrome (CFS), Human Herpes Virus-6 (HHV6), luciferase immunoprecipitation
systems (LIPS)
Address all correspondence to:
Dr. James Baraniuk, Division of Rheumatology, Immunology and Allergy, Room 3004F, 3rd Floor, PHC Building,
Georgetown University, 3800 Reservoir road, NW, Washington, D.C. 20007-2197. Tel (202)-687-8231; Fax
(202)-687-9886; E-mail: baraniuj@georgetown.edu
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