Gavin Giovannoni, MBBCh, of Barts and the London School of Medicine and Dentistry in London, who also helps lead the raltegravir trial with Gold, told MedPage Today that all herpes viruses, of which EBV is one, can trigger HERV expression. But, he said, "EBV is particularly effective in activating HERVs."
Also, according to Gold, HERV expression has been linked to activation of both the innate and adaptive immune systems, providing a connection to the well-documented immunological and inflammatory features of MS.
Although the HERV theory doesn't explain everything about MS, such as the gender imbalance, Giovannoni said the conventional autoimmune paradigm has "lots of holes" too.
"It doesn't explain everything about MS, and as part of a causation theory it should explain everything. It doesn't explain the epidemiology very well, it doesn't explain the sex ratio, it doesn't explain some of the responses to certain therapies," he said.
"That's a clue that we don't know the whole story."
The HIV Connection
Perhaps the most significant piece of evidence for the HERV theory of MS is even more indirect: People with HIV appear to be at vastly reduced risk for MS.
What does HIV status have to do with HERVs or MS? Because nowadays, essentially everyone with HIV in developed countries where broad-based epidemiological research can be conducted is treated with antiretroviral drugs.
Gold is an HIV specialist -- the Albion Street Centre, which he directs, is Australia's largest HIV outpatient clinic. His "aha" moment came when an HIV-positive patient who also had MS came under his care. This patient was first diagnosed with HIV infection in 1985 but managed to avoid developing AIDS before the advent of highly active antiretroviral therapy (HAART) in 1996.
In a 2011 letter published in the European Journal of Neurology, Gold and colleagues described what happened after HAART was begun in 1996:
"Within months of commencing HAART, all MS symptoms gradually improved. Within 2 years, his urinary incontinence was controlled to the extent that he stopped wearing pads and fecal incontinence resolved. He has had no MS relapses."
The disease was not completely eliminated, the researchers indicated, because gadolinium-enhanced MRI scans made in 2002 continued to show lesions consistent with MS, even though clinical symptoms had largely disappeared.
Large-scale epidemiological studies have supported the notion that anti-HIV therapy may suppress MS pathology. A Danish national registry study published in letter form last year in Epidemiology, comparing 5,018 HIV-positive patients with some 50,000 age- and sex-matched individuals from the general population, found that the rate of MS incidence was markedly lower in the HIV patients (3.1 versus 10.4 per 100,000). However, it was not statistically significant because only one HIV patient developed MS during the study period.
Gold and colleagues conducted a similar (but as yet unpublished) study using the much larger U.K. general practice database, which covers some 55 million Britons. At the European MS meeting where he spoke last fall, he reported on results from some 21,000 HIV-positive individuals and 6.7 million controls, followed for a mean of 7 years.
In addition to matching controls to HIV patients by age and sex, they were also matched by region within the country and by the week in which they first came into contact with the national health system.
The relative risk for MS in the HIV patients versus controls was 0.38 (95% CI 0.15-0.79, P=0.011), he reported. The relative risk was even lower, 0.22, when only MS diagnoses occurring more than 1 year after HIV diagnosis were counted (at which point HAART is presumably well established in British HIV patients).
The Clinical Trials
There is no animal model for HERVs in MS, and the ability to study HERVs even in cell culture is limited, Gold said. He argued that "their exact role will only be obtained following appropriate clinical trials. If we wait for the laboratory to give us the answer, we will all have been retired."
Raltegravir was chosen for the U.K. trial for several reasons. One is that it is an HIV integrase inhibitor. "The integrases across HERVs and HIV are quite conserved," Giovannoni said, so that it is likely to be more effective in suppressing HERV elements than other types of antiretroviral drugs. He said it was also unique among antiretrovirals in also showing some potency against members of the herpesvirus family (though only in vitro -- this effect hasn't been studied clinically).
And, its manufacturer was willing to support the small, short-term trial. Gold pointed out that no company that markets MS medications is active in HIV drug development, or vice versa. He and Giovannoni were able to persuade raltegravir's maker, Merck's European subsidiary, to fund the 25-patient study which includes just 3 months of drug treatment after a 3-month baseline observation period. Gold said a longer and larger study would have been preferable but it could not be arranged...
... Serra said he hoped that the two clinical trials wouldn't be taken as make-or-break for the HERV theory. "We need more rigorous models, especially animal models that have been lacking so far. I know there are groups that are looking into it."
http://www.medpagetoday.com/Neurology/MultipleSclerosis/44861
