The evidence continues to mount that herpesviruses HHV-6A, EBV and VZV play an important role in triggering multiple sclerosis, perhaps in different subsets. Researchers at Oregon National Primate Research Center recently isolated a gamma herpesvirus that caused symptoms identical to MS in macaque monkeys. Alberto Ascherio at Harvard has shown that elevated EBV EBNA-1 antibodies are a marker for increased risk of MS, and researchers in Mexico recently found that VZV DNA is found in the CSF of 65% of MS patients with the progressive form and Chinese investigators found an increased incidence of MS the year after a VZV shingles attack.
The evidence for HHV-6A seems strongest of all the viruses implicated, although these viruses potentiate each other and co-infections and interaction with endogenous retroviruses appear to play a role as well. Over the past five years, European researchers have shown that HHV-6A can be isolated from the serum and CSF in a subset of MS patients during relapse, and have linked HHV-6A reactivation to two genes associated with an increased risk for MS: IRF5 and MHC2TA rs4774C.
Steve Jacobson at NINDS has shown that there is an increased lymphoproliferative response to HHV-6 and that there are HHV-6 and EBV specific oligoclonal bands in MS patients. Finally, the Spanish investigators also demonstrated that the effectiveness of interferon beta 1b treatment in MS patients correlates with HHV-6 DNA levels, suggesting that it is the antiviral action of the interferon beta treatment that causes the therapeutic effect. Jacobson’s group presented evidence at the last HHV-6 conference last winter that HHV-6A can cause MS-like neurological disease in monkeys (unpublished), and a group from France demonstrated that HHV-6A can cause mice to develop lesions in the brain.
Where is the MS community and why aren’t patients demanding clinical trials with antivirals? Clinicians at NYU tried valacyclovir (Valtrex) in 2005, but this was the wrong drug. Valtrex (which converts to acyclovir) is not effective for HHV-6. The rationale for a trial of valganciclovir (Valcyte) is compelling. It crosses the blood brain barrier, has a relatively good safety profile, and is effective against HHV-6A. FDA approved for CMV retinitis, Valcyte is an oral drug that can be used safely as long as patients are monitored for bone marrow suppression. It has been used routinely as prophylaxis for herpesvirus reactivation in the transplant community for over ten years, with minimal adverse side effects.
The HHV-6A may only be a bystander, and it may be that abortive infection (not actual replication) is what is important in triggering MS. That doesn’t mean an HHV-6 and EBV specific antivirals shouldn’t be given a try – especially in those with signs of viral activity (elevated IgG titers or virus specific oligoclonal bands). It is pretty clear now that interferon works for MS because of the antiviral effect, but it is a relatively weak antiviral compared to the others used for viral reactivation in transplant patients. What are neurologists waiting for?
HHV-6A and HHV-6B to be recognized as two distinct viruses
Philip Pellett, Chair, Herpesvirales Working Group
Phil Pellet, the chair of the Herpesvirales Study Group of the International for Taxonomy of Viruses (ICTV, ictvonline.org), announced at the 7th International Conference on HHV-6 & 7 that the Study Group has recommended that HHV-6A and HHV-6B be recognized as two distinct viruses. The final decision will be made by the ICTV Committee this year.
The announcement came a year after a group of 18 leaders in the field of HHV-6 research petitioned the Study Group to officially recognize the two “variants” as separate species.
HHV-6B causes 97 – 100% of primary iHHV-6 infections in the USA and Japan and is responsible for a comparable percentage of transplant reactivation cases. HHV-6B, but not HHV-6 has been associated with febrile seizures, mesial temporal lobe epilepsy and status epilepticus
HHV-6A has been found more frequently in patients with neuroinflammatory diseases such as a patients with multiple sclerosis (MS) and children with rhomboencephalitis. HHV-6A is acquired later in life, usually without clinical symptoms, except in Sub-Saharan where HHV-6A is acquired earlier and causes roseola (instead of HHV-6B) in the majority of the pediatric population
HHV-6B is more prevalent than HHV-6A in the peripheral blood mononuclear cells of healthy adults and transplant patients, while HHV-6A is found more frequently in the plasma of HSCT patients. HHV-6B but not HHV-6A is commonly found in saliva. HHV-6A, but not HHV-6B can productively infect CD8+ T-cells, natural killer cells, and γ/δ (gamma/delta) T-cells.
HHV6-A will generally not infect cell lines readily infected by HHV-6 B and vice versa. There are also several monoclonal antibodies that will only interact with one or the other.
All HHV-6 isolates including those found in chromosomally integrated HHV-6 can be clearly designated either A or B. The IE1 gene shows 30% divergence between the two new species, but is very stable (>95%) within the clinical and laboratory isolates of each species.
Unfortunately, many HHV-6 publications do not specify which virus was used in the research. The authors of the petition on HHV-6A and HHV-6B, listed below, urge all of HHV-6 investigators to specify whether their research relates to HHV-6A or HHV-6B. Anyone interested in learning more details about the arguments to identify the two “variants” as two separate species, should contact the Committee Co-Chairs Dario Di Luca or Dharam Ablashi.
Ad Hoc Committee on HHV-6A & HHV-6B Genomic Divergence
Dharam Ablashi, DVM, HHV-6 Foundation, Santa Barbara, USA (Co-chair)
Henri Agut, MD, PhD, Hospital Pitie-Salpetriere, Paris, France
Yoshizo Asano, MD, PhD, Fujita Health University, Toyoake, Aichi, Japan
Roberto Alvarez-LaFuente, MD, Hospital Clinico San Carlos, Madrid, Spain
Don Carrigan, PhD, Wisconsin Viral Research Group, Milwaukee, USA
Duncan Clark, PhD, Royal Free & University College Medical School, London, UK
Dario Di Luca, PhD, University of Ferrara, Ferrara, Italy (Co-Chair)
Steve Dewhurst, PhD, University of Rochester, USA
Louis Flamand, PhD, University Laval, Quebec, Canada
Niza Frenkel, PhD, Tel Aviv University, Tel Aviv, Israel
Robert Gallo, MD, Institute of Virology, University of Maryland, USA
Ursula Gompels, PhD, London School of Tropical Medicine, London, UK
Caroline Hall, MD, University of Rochester, Rochester, USA
Steve Jacobson, PhD, National Institute of Neurological Disorders & Stroke/NIH, Bethesda, USA
Kazuhiro Kondo, MD, PhD, Jikei University School of Medicine, Tokyo, Japan
Mario Luppi, MD, PhD, University of Modena and Reggio Emilia, Modena, Italy
Paolo Lusso, MD, PhD, National Institute of Allergy and Infectious Diseases/NIH, Bethesda, USA
Yasauki Mori, MD, PhD, National Institute of Biomedical Innovation, Osaka, Japan
Koichi Yamanishi, MD, PhD, National Institute of Biomedical Innovation, Osaka, Japan
Tetsushi Yoshikawa, MD, Nagoya University School of Medicine, Toyoake Aichi, Japan