I wasnt super thrilled about the last ERV–>MS paper I wrote about, but I really like this new one:
Those of you who have been following the XMRV fiasco will find this intro paragraph very interesting:
When the first descriptions of retrovirus-like particles with reverse-transcriptase (RT) activity in leptomeningeal and macrophage cell cultures from patients with multiple sclerosis (MS) were published they were thought to be related to a new human T-lymphotropic virus (HTLV) supposed to explain analogies between HTLV type 1 associated myelopathy and MS. After preliminary biological characterization of this MS-associated retroviral element (MRSV), molecular analysis of its genome revealed quite a complex picture as the MSRV genome had endogenous counterparts in human DNA featuring a Human Endogenous Retrovirus (HERV). Instead of the expected HTLV virus, it represented an element from a previously unknown HERV family, now named HERV-W.
Transport yourself to 1989. You take brain and blood cells out of MS patients… and find reverse transcriptase activity. You can find RT activity and viral genome associated with viral particles. HTLV and HIV are all the rage, so youre thinking you found a new retrovirus. Other labs in other parts of the world can replicate your findings. Other labs around the world figure out a potential mechanism for disease– the envelope protein is pro-inflammatory. Its probably the viral protein causing trouble. Theres only one problem: When you do all the proper controls for your PCR experiments, you are finding sequences that look like your ‘new’ virus in human DNA. There is no human genome project yet, but we know that there are endogenous retroviruses in human DNA. So you dont conclude that there is a massive, world-wide conspiracy against you, you conclude that the offending agent isnt a ‘new’ retrovirus at all, but a million year-old endogenous retrovirus that has somehow become activated in MS patients, and might/might not be directly contributing to disease. So you spend the next couple of decades trying to figure it out.
I think this paper, while not a sexah Nature or Science or Lancet or whatever paper, is an honorable contribution to the foundation of work the ‘MSRV’ researchers set in 1989. Its practical and thorough.
MS patients + appropriate controls (not only healthy controls, but control samples from patients with other neurological and non-neurological diseases):
Samples comprised (i) other neurological diseases (OND): 20 patients with epilepsy, chronic polymyositis, primary cerebral tumour, sciatica, Guillain-Barré Syndrome, stroke, multisystem atrophy, facial palsy, amyotrophic lateral sclerosis (ALS), cerebral metastasis (lung cancer), Leigh’s disease, traumatic medullar lesion, cerebral abcess (listeria), together with eight patients with chronic inflammatory demyelinating polyneuropathy (CIDP); (ii) non-neurological diseases (NND): 15 patients with chronic hepatitis B virus infection, 15 with chronic hepatitis C virus infection, 30 with systemic lupus erythematosus (SLE); and (iii) healthy blood donors: 60 HC.
They also used multiple avenues of blinded detection: ELISA, quantitative real-time PCR, RT-PCR
What they found: In the pilot study, 23 of 29 MS patients were positive by ELISA (had HERV-W Env expressed in their blood cells). Other groups from other locations got 59 of 74. Some of their diseased controls, like the CIDP patients, for instance, were also positive (5 of 8). The healthy patients were used to set baseline, but none of the diseased (hepatitis B patients, for instance) were Env postitive.
This is where the diseased controls are important– The lupus, hepatitis, etc controls were NOT HERV-W positive. Because, an alternative conclusion could be that any chronic disease leads to some kind of epigenetic disregulation and Env is expressed, rather than Env being expressed is causing disease. If the patients with other chronic diseases do NOT have Env present, then there is more weight towards the hypothesis that HERV-W is causing trouble in MS patients, not the other way around.
So in summary, 80% of the MS patients had HERV-W Env protein.
In quantitative real-time PCR for both RNA expression and DNA copy number, 40% of MS patients were increased relative to healthy controls, whereas 4% of the blood donors were increased.
While this is all find and dandy, its a meaningless trick without some connection to the brain.
As it is relatively difficult to get brain samples from living donors, the investigators looked at the brains of 8 MS patients who had donated their bodies to science after death. They found that HERV-W was expressed on the macrophages and the activated microglial cells present at active MS lesions in the brain. They got the same results with three different anti-env antibodies, and different macrophage markers, in all eight brains.
This paper made a direct, clear connection between what we had been observing in blood samples with what is going on in the brain. Its the macrophages and microglial cells (macrophages that are specific to the brain), that are expressing HERV-W in the brain. We can test for the ‘brain’ phenotype by looking in the blood. You dont have to go into CSF. You dont have to wait and look at brains when the patient is dead. They also came up with this theoretical model of disease.
And they mentioned something I have not heard before… Anti-HERV-W antibodies are in clinical trials for MS patients…
I like this paper 🙂