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

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