Multiple sclerosis is a disease that affects a large patient population, but as pointed out by Jerry Wolinsky, MD, from the University of Texas Health Science Center, the decade-long search for multiple sclerosis triggers has ended up in many blind alleys. One trigger that has received relatively little attention from the scientific community is the activation of human endogenous retroviruses (HERVs), which are remnants of retroviruses that infected our ancestral humans and became incorporated into the human genome. Up to 8% of the entire genome encodes retroviral elements, and although they are assumed to be nonfunctional, research indicates that they become activated to express proteins.
Two clinical trials abroad are pursuing the theory of a role for HERVs in multiple sclerosis onset. One group in the United Kingdom is evaluating the HIV drug raltegravir (Isentress) in 25 multiple sclerosis patients. The trial will conclude in August, and the measured outcome concentrates on brain lesions seen in MRI scans. Another group in Sweden from GeNeuro Innovationis evaluating the safety of a monoclonal antibody called GNbAC1 that targets a specific HERV element. The results will be revealed in April at the American Academy of Neurology’s annual meeting.
It has yet to be proven that HERVs are pathogenic, and the leader of the UK trial, Julian Gold, MBBS, MD, from the Albion Street Centre in Sydney, Australia, says that current laboratory methods cannot provide such proof, at least in the case of multiple sclerosis. However, there is mounting evidence that HERV proteins, including Epstein Barr virus, exist in multiple sclerosis lesions. According to Gavin Giovannoni, MBBCh, from Barts and the London School of Medicine and Dentistry, “EBV is particularly effective in activating HERVs,” and HERV expression has been linked to activation of the innate and adaptive immune systems. Since multiple sclerosis is an autoimmune disease, these findings suggest a connection to the immunological and inflammatory features of multiple sclerosis. However, “it does not explain everything about multiple sclerosis, and as part of a causation theory it should explain everything. It does not explain the epidemiology very well, it does not explain the sex ratio, it does not explain some of the responses to certain therapies,” said Giovannoni.
The most telling piece of evidence for the HERV theory is people with HIV are at a vastly reduced risk for multiple sclerosis. One anecdotal example comes from Gold’s practice at the Albion Street Centre, which is Australia’s largest HIV outpatient clinic. A patient with multiple sclerosis was diagnosed with HIV in 1985 and began highly active antiretroviral therapy (HAART) in 1996. As reported by Gold and colleagues in 2011 in the European Journal of Neurology, “Within months of commencing HAART, all multiple sclerosis symptoms gradually improved…. He has had no multiple sclerosis relapses.” However, the disease was not completely eliminated, as evidenced by MRI scans of lesions. Larger-scale epidemiological studies have also reported that anti-HIV therapy suppresses multiple sclerosis pathology.
No animal model for HERVs in multiple sclerosis exists, and studying HERVs in cell culture is limited. Said Gold, “[the role of HERVs] 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.” Clinical trials must therefore be designed with care. The UK study chose raltegravir because it is an HIV integrase inhibitor. “The integrases across HERVs and HIV are quite conserved,” said Giovannoni. They are likely more effective in suppressing HERV elements than other antiretroviral agents. Additionally, the manufacturer is supporting the short-term trial, which is unique because no company that markets multiple sclerosis drugs develops drugs for HIV, and vice versa.
With any theory yet unproven comes a note of caution. According to Alessandro Serra, MD, from University Hospitals Case Medical Center in Cleveland, HERVs appear “in patients with other neurological conditions, and even in a proportion of healthy individuals,” indicating that HERVs may not be intimately linked with multiple sclerosis. The real debate is “whether HERVs are just bystanders within the normal immune response of MS patients, perhaps unable to handle these viruses, or whether they actually represent a key component of the pathogenic process of MS and even have a causative role.” Adds Wolinsky, “To my knowledge there has been no consistently recovered retrovirus sequence associated with brain or other tissues from patients with multiple sclerosis…. The course of multiple sclerosis is very unpredictable.” Certainly, “we need more rigorous models, especially animal models that have been lacking so far,” said Serra. Perhaps then the theories surrounding HERVs and multiple sclerosis will be bolstered.