Virus, virus where art thou hiding?

Barts-MS rose-tinted-odometer: ★★★★★★★★★★

Would you volunteer to participate in a clinical trial of an antiviral drug cocktail to suppress MS disease activity, in particular smouldering MS?

There is reasonable evidence in the literature that HERVs (human endogenous retroviruses) may play a role in autoimmunity, in particular MS. HERVs are viruses (genetic code) that have been incorporated into the human genome over deep time. Some HERV genetic elements have taken on important functional roles, for example, they are involved in the development of the mammalian placenta and hence are part of our human biology. 

When HERVs elements are transcribed they may be capable of forming replication-competent viruses, which can reinfect cells and integrate back into the genome. These reintegration sites may be important in themselves and may drive the selection of cells with enhanced functions and may also result in cancer. Other HERV elements are replication-incompetent and although they can produce functional transcripts can’t form an infectious virus. 

Some HERV proteins act as danger signals activating so-called toll-like receptors and other danger-signalling pathways. These pathways then upregulate innate immunity and provide the immunological nudge that drives autoimmunity. This is why there have been some attempts to try and suppress HERV activation with antiviral drugs or to neutralise some of the HERV proteins that may activate the immune system, or are directly toxic to myelin-producing cells and/or neurones, as a treatment for MS. 

These HERV-related hypotheses are supported by several studies showing upregulation of HERVs transcripts and HERV proteins in the brains of people with MS. The study below uses a new technology called next-generation RNA sequencing to show that some HERV-W (a specific type of HERV) transcripts are exclusively present in MS brains and as they are located on chromosome 7 close to one of the MS genetic risk loci may be relevant to MS. Could this finding be part of the proof we need to show that HERV-W may be in the causal pathway that leads to the development of MS? Importantly, HERV transcripts (RNA message) close to the MS risk locus on chromosome 7 were overrepresented in MS brains. 

Although some would interpret these findings as being potentially causal, i.e. HERV transactivation and expression is driving the pathology that is MS, another interpretation is that whatever causes MS transactivates HERVs, which is then simply a bystander phenomenon. The only way to separate ‘causation’ from ‘association’ is to do an experiment to suppress HERV transactivation to see if it improves MS outcomes. This is a conclusion that Prof. Julian Gold and I came to several years ago and is why we have been trying to get funding to do a CNS penetrant combination antiretroviral trial in MS.

Some of the cynics will ask ‘well what about your EBV hypothesis’? Interestingly, EBV and some of the other herpes viruses are potent transactivators of HERVs, i.e. infection with EBV wakes-up HERVs in our genome and results in their transcription. Therefore, increased HERVs may be a marker of EBV infection. This may be important, but recent data indicates that some HAART (highly active antiretroviral therapies) components are also effective against EBV. Therefore, clinical trials of HAART may actually target both EBV and HERVs. This is why I am so excited about the news that a small HAART trial in MS will be starting soon in the US.  However, Prof. Julian Gold and I, as part of our Charcot Project, will still continue to prod and encourage big Pharma companies (ViiV-GSK, Gilead, Merck, etc.) with a footprint in the antiretroviral space, to come to the table with their products (HAART) and money to fund a large adequately powered study to test the hypothesis in a definitive MS study. 

It would be a travesty if in 20 years time the next generation of MS researchers discover that HAART is a very effective treatment for MS when we have the tools to answer this question now, i.e. in the next 4 to 5 years? In fact, we have a clue that this may be the case already. Having HIV infection protects one from getting MS. This may be due to the therapy (HAART) that is used to treat HIV and not due to the HIV virus itself. 

As you know outside-the-box ideas or paradigm shifts often take generations to occur. So you shouldn’t be surprised if the MS community continues to reject these hypotheses and nothing happens for decades.   

Maria L Elkjaer et  al. Unbiased examination of genome-wide human endogenous retrovirus transcripts in MS brain lesions. Mult Scler. 2021 Jan 19;1352458520987269. doi: 10.1177/1352458520987269. 

Background: Human endogenous retrovirus (HERV) expression in multiple sclerosis (MS) brain lesions may contribute to chronic inflammation, but the expression of genome-wide HERVs in different MS lesions is unknown.

Objective: We examined the HERV expression landscape in different MS lesions compared to control brains.

Methods: Transcripts from 71 MS brain samples and 25 control WM were obtained by C and mapped against HERV transcripts across the human genome. Differential expression of mapped HERV-W and HERV-H reads between MS lesion types and controls was analysed.

Results: Out of 6.38 billion high-quality paired-end reads, 174 million reads (2.73%) mapped to HERV transcripts. There was no difference in HERVs expression level between MS and control brains, but HERV-W transcripts were significantly reduced in chronic active lesions. Of the four HERV-W transcripts exclusively present in MS, ERV3633503 located on chromosome 7q21.13 close to the MS genetic risk locus had the highest number of reads. In the HERV-H family, 75% of transcripts located to nearby 7q21-22 were overrepresented in MS, and ERV3643914 was expressed more than 16 times in MS compared to control brains. 

Conclusion: Novel HERV-W and HERV-H transcripts located at chromosome 7 regions were uniquely expressed in MS lesions, indicating their potential role in brain lesion evolution.

CoI: multiple

Twitter: @gavinGiovannoni                                    Medium: @gavin_24211

Black Swan?

Is this the black swan I have been looking for?

We need to be able to explain smouldering MS and why pwMS get worse despite having no evident disease activity (NEDA) on DMTs. One of the hypotheses is that something is occurring within the brains and spinal cords of pwMS. I have referred to this in the past as the field hypothesis and have suggested that it could be due to an active virus within the brains of pwMS. I have always made the point that the two viruses with most of the evidence behind them are EBV and HERVs, particularly HERV-W.

This study below strongly suggests that the HERV-W envelope protein may be driving smouldering MS. It would be interesting if the ENV protein is found in SELs (slowly expanding lesions). This study supports our Charcot Project and the urgent need to formally test HAART (highly active antiretroviral therapies) in MS. Our INSPIRE trial, which was negative, was not HAART as it only tested one anti-retroviral and integrase inhibitor.

Do you have the appetite for another push at getting funding for an add-on HAART trial in MS? The case for doing it is compelling both from an epidemiological and basic science perspective.

LET’S DO IT!

Kremer et al. pHERV-W envelope protein fuels microglial cell-dependent damage of myelinated axons in multiple sclerosis. Proc Natl Acad Sci U S A. 2019 Jun 18

Axonal degeneration is central to clinical disability and disease progression in multiple sclerosis (MS). Myeloid cells such as brain-resident microglia and blood-borne monocytes are thought to be critically involved in this degenerative process. However, the exact underlying mechanisms have still not been clarified. We have previously demonstrated that human endogenous retrovirus type W (HERV-W) negatively affects oligodendroglial precursor cell (OPC) differentiation and remyelination via its envelope protein pathogenic HERV-W (pHERV-W) ENV (formerly MS-associated retrovirus [MSRV]-ENV). In this current study, we investigated whether pHERV-W ENV also plays a role in axonal injury in MS. We found that in MS lesions, pHERV-W ENV is present in myeloid cells associated with axons. Focusing on progressive disease stages, we could then demonstrate that pHERV-W ENV induces a degenerative phenotype in microglial cells, driving them toward a close spatial association with myelinated axons. Moreover, in pHERV-W ENV-stimulated myelinated cocultures, microglia were found to structurally damage myelinated axons. Taken together, our data suggest that pHERV-W ENV-mediated microglial polarization contributes to neurodegeneration in MS. Thus, this analysis provides a neurobiological rationale for a recently completed clinical study in MS patients showing that antibody-mediated neutralization of pHERV-W ENV exerts neuroprotective effects.