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evidence at the last HHV-6 conference last winter that HHV-6A can cause MS-like neurological disease in monkeys (unpublished), and a group from France demonstrated that HHV-6A can cause mice to develop lesions in the brain.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?
More than enough evidence that HHV-6A triggers MS in a significant subset? Time for a clinical trial?
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?