Inspire, expires: The first breath of the Charcot Project

Is MS a problem caused by a virus?

Is the world flat?

The INSPIRE trial set out to investigate one of these following an anecdote that a person, who had MS but was treated with HIV-inhibiting treatment, did well. 

Was this a fluke or the beginning of a new era in MS research?

You know the answer. Yep, the trial was not a success.

This study looked at raltegravir, rather than looking at HAART, which is a cocktail of drugs used to inhibit HIV.

Why? Because a company making raltegravir sponsored the study. 

However, raltegravir is an integrase inhibitor. This means it aims to stop virus integrating into the host's genome to cause infection. 

This is what HIV does to infect. 

However for a human endogenous retrovirus, the virus integrated probably a few thousand years ago. Other viruses may not integrate. Therefore would raltegravir be the most logical choice of an anti-viral? Perhaps not.

So whilst the trial failed it does not say the idea of a viral cause of MS is dead.

The paper is available to download and read.

A phase II baseline versus treatment study to determine the efficacy of Raltegravir (Isentress) in preventing progression of relapsing remitting multiple sclerosis as determined by gadolinium-enhanced MRI: 

Julian Gold, Monica Marta, Ute C. Meier, Tove Christensen, David Miller, Daniel Altmann
David Holden, Lucia Bianchi, Rocco Adiutori, David MacManus, Tarek Yousry, Klaus Schmierer
Benjamin Turner, Gavin Giovannoni


Although the aetiology of multiple sclerosis (MS) remains elusive, it is clear that Epstein Barr virus (EBV) and possibly other viruses play a role in the pathogenesis of MS. Laboratory evidence suggests that human endogenous retroviruses (HERVs) could also have a role, but no interventional therapy has determined what will happen if HERVs are suppressed. Recent epidemiological evidence indicates patients with HIV infection have a significantly lower risk of developing MS and that HIV antiretroviral therapies may be coincidentally inhibiting HERVs, or other retroelements, that could be implicated in MS.


To systematically investigate the effects of an HIV integrase strand inhibitor, raltegravir, on the number of gadolinium (Gd)-enhanced MRI lesions in people with active relapsing MS.


This is a Phase 2a clinical trial where twenty participants were enrolled in a 3 month baseline phase followed by 3 months of treatment with raltegravir 400 mg twice a day. Patients had monthly Gd-enhanced MRI, saliva collection to test for EBV shedding, blood sampling for safety monitoring, virology (including HERVs), measurement of immunological and inflammatory markers; and physical, neurological and quality-of-life assessments.


All patients completed the six months trial period.The primary outcome measure of MS disease activity was the number of Gd-enhancing lesions observed, and raltegravir had no significant effect on the rate of development of Gd-enhancing lesions during the treatment phase compared with the baseline phase. Additionally, there was no change in secondary outcomes of either disability or quality-of-life measures that could reasonably be attributed to the intervention. There was a significant positive between HERV-W/MSRV (multiple sclerosis related virus) Gag Flix (Fluorescence index) B cells and the number of Gd-enhanced lesions at any visit (p = 0.029), which was independent of any potential influence of the trial drug administration. Regarding EBV shedding, there was no significant correlation between the amount of EBV shedding and the number of lesions. No change was detected in inflammatory markers (IL-8, IL-1β, IL-6, IL-10, TNF, IL-12p70 and HCRP), which were all within normal limits both before and after the intervention. Serum CD163 expression was also unchanged by raltegravir.


Raltegravir did not have any impact on MS disease activity. This could be due to the choice of antiretroviral agent used in this study, the need for a combination of agents, as used in treating HIV infection, the short treatment period or dosing regimen, or the lack of a role of HERV expression in MS once the disease is established. Borderline significance for the association between EBV shedding and the total number of lesions, probably driven by new lesion development, may indicate EBV shedding as a marker of inflammatory disease activity. In conclusion, interesting correlations between HERV-W markers, EBV shedding and new MRI lesions, independent from treatment effects, were found.
The INSPIRE Study is now available online, containing full bibliographic details:

CoA: This is work by the ProfGs and other members of the team. This is disappointing, but if you don't try you can't fail, although importantly you can never succeed.