Can any antivirals kill/inhibit EBV (Epstein Barr Virus)?

[Jaybee00]

Seems like the literature is confusing here. Consensus seems to be that no antivirals (AV) are effective against EBV.

Novel Therapeutics for Epstein–Barr Virus - PMC

Epstein–Barr virus (EBV) is a human γ-herpesvirus that infects up to 95% of the adult population. Primary EBV infection usually occurs during childhood and is generally asymptomatic, though the virus can cause infectious mononucleosis in 35–50% of ...

pmc.ncbi.nlm.nih.gov

But then there are case studies showing certain AVs are effective.

https://academic.oup.com/jid/article/216/2/198/3858428

https://ashpublications.org/blood/article/138/Supplement%201/4863/481836/High-Dose-Intravenous-Acyclovir-Is-Safe-and

Frontiers | Antiviral treatment with valacyclovir reduces virus shedding in saliva of Antarctic expeditioners

Reactivation of herpes viruses such as Epstein-Barr virus (EBV), herpes simplex virus 1 (HSV1), and varicella zoster virus (VZV) increase in astronauts durin...

www.frontiersin.org

https://www.neurology.org/doi/10.1212/01.wnl.0001051656.33616.15

https://journals.asm.org/doi/10.1128/jvi.01005-09

Acyclovir as a Novel Treatment for Severe Chronic Active Epstein-Barr Virus

Epstein-Barr virus (EBV) is a widely infectious pathogen affecting most of the global population at some point in their life. While, typically, primary infections are subclinical, chronic persistence of the virus due to T-cell proliferation can cause severe complications. Acute hepatitis due to...

www.cureus.com

More recently, evidence is presented that that tenofovir prodrugs tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF), are highly effective against EBV (in vitro)

Tenofovir prodrugs potently inhibit Epstein-Barr virus lytic DNA replication by targeting the viral DNA polymerase - PubMed

Epstein-Barr virus (EBV) is a ubiquitous human γ-herpesvirus that establishes life-long infection and increases the risk for the development of several cancers and autoimmune diseases. The mechanisms by which chronic EBV infection leads to subsequent disease remain incompletely understood. Lytic...

pubmed.ncbi.nlm.nih.gov

In vivo

https://www.sciencedirect.com/science/article/abs/pii/S2211034824000154

Trial

Effects of Antiviral Therapies on Epstein-Barr Virus Replication

This research study is being performed to find out if Truvada (tenofovir/emtricitabine), an antiviral drug with activity against the Epstein Barr virus (EBV), can reduce EBV levels in saliva and blood in people with multiple sclerosis (MS). A second goal is to find out if Truvada (tenofovir/...

ctv.veeva.com

Does anyone have any idea on the current thinking/consensus (if any) on this topic?

 

[Jonathan Edwards]

Rituximab clears EBV effectively in the context of transplantation.

 

[Kiki AU]

I have personal experience of Paxlovid (antivirals used for Covid) providing a step change improvement in my functional capacity, with PacMan Super Powers for about 4 weeks post completion of the 5 day course, but a lasting impact where I am improved from the previous baseline. My pharmacist suggested Tenofovir might provide similar lasting effects. I'm only 2 weeks into a trial and do seem to be sustaining better capacity, so very interested in any other evidence for ongoing use of TAF

 

[Hutan]

Welcome to the forum @Kiki AU, thanks for sharing your experience. Can I ask, how long have you been ill for? A lot of people recover naturally in the first couple of years of their illness.

Rituximab clears EBV effectively in the context of transplantation.

That seems important information, relevant to hypotheses that latent infections of EBV are causing ME/CFS (with rituximab seeming to not bring about a significant improvement in people with ME/CFS). Are courses of rituximab (dosage, treatment length, accompanying drugs) that clear EBV prior to transplantation different to what was tried by Fluge and Mella? How effective and lasting is the 'clearance'?

 

[Jonathan Edwards]

Are courses of rituximab (dosage, treatment length, accompanying drugs) that clear EBV prior to transplantation different to what was tried by Fluge and Mella? How effective and lasting is the 'clearance'?

I think the doses are the same. My memory is that Dorothy Crawford in Edinburgh was involved in the EBV clearance studies. I think they were treating BM transplant patients who had uncontrolled EBV proliferation in the context of the immunosuppression used. Rituximab cleared EBV sufficiently to abort the problem - presumably despite ongoing immunosuppressive state and suggesting complete clearance of replicating virus.

My understanding in relation to EBV and ME/CFS is that Lipkin's group failed to find any evidence of more EBV in ME/CFS. I think it is hard to blame EBV with a straight negative on that.

 

[Hutan]

I guess it might not be a case of more EBV in ME/CFS, but where it is, and what the body's response to it is. The failure of rituximab to improve ME/CFS might not rule out a latent infection of neurons or the cells beside them ( and so affecting signals e.g. 'invoke sickness behaviour'), without causing any release of the virus into blood. ?

 

[Jonathan Edwards]

I guess it might not be a case of more EBV in ME/CFS, but where it is, and what the body's response to it is. The failure of rituximab to improve ME/CFS might not rule out a latent infection of neurons or the cells beside them ( and so affecting signals e.g. 'invoke sickness behaviour'), without causing any release of the virus into blood. ?

I think that is stretching what we know of biological possibility to the limit. OK there might be wild pussycats in Antarctica but what we know makes it pretty unlikely.

 

[forestglip]

I think that is stretching what we know of biological possibility to the limit.

Could you explain more about why it's implausible?

 

[Jonathan Edwards]

Could you explain more about why it's implausible?

For a virus to actually cause trouble it really needs to be replicating or at least translating nucleic acid into proteins. Retroviruses are maybe a bit different but EBV is not a retrovirus. When viruses like varicella are latent in nervous tissue they are silent. It is when they replicate that they produce shingles or cold sores. As far as I know we know enough about the behaviour of EBV to say that it is very unlikely to be hiding latent in neural tissue (rather than its favoured B cells) and yet causing symptoms like ME/CFS. If it were producing symptoms I think you would expect some signal of increased amounts of its DNA or proteins in the circulation.

And other things don't provide support. When people with immunosuppression have EBV starting to replicate they don't have ME/CFS, although they may feel fairly crummy from whatever disease they had. I don't think you get brain or nerve problems particularly, although I may be wrong about that. If latent EBV in brain was a thing I think I would have heard all about it - living in a house with an EBV expert as a mother.

 

[jnmaciuch]

I guess it might not be a case of more EBV in ME/CFS, but where it is, and what the body's response to it is. The failure of rituximab to improve ME/CFS might not rule out a latent infection of neurons or the cells beside them ( and so affecting signals e.g. 'invoke sickness behaviour'), without causing any release of the virus into blood. ?

It’s a tricky question but not completely outside the realm of possibility. I ended up chatting to a virology postdoc about this a few weeks ago because she studies EBV latency and I had some questions about how EBV modulates the cellular interferon response. EBV is perfectly capable of infecting neurons, it just doesn’t seem to be the preferred breeding ground in most cases. However, there’s not much evidence that neurons are able to sustain long term latent infection—EBV is pretty specialized to use the machinery of B cells to maintain its latency.

It would pretty much have to be in the latent state, otherwise ME/CFS would be characterized by progressive neurological worsening. Though just because it hasn’t been observed in cultured neurons doesn’t mean it can never happen, and it could also be possible for latent infection to be sustained in other non-neuronal cells in the CNS.

It’s a common misconception that latent viruses are fully transcriptionally silent. Nearly all of them actively transcribe genes meant to affect the host cell and maintain ideal conditions for the viral genome to stay latent—there’s been a lot of work in the past two decades characterizing these dynamics for different viruses. Continuous production of LMP1 by latent EBV and subsequent post-translational modifications of interferon signaling molecules is one well-known example of this. This could be easily missed if mRNA screens are only looking for genes active in the lytic phase—and it’s also entirely possible for that mRNA to only reach detectable levels in the CSF and not the blood.

But this latent signaling would occur in both ME/CFS and healthy cases, so the big burden on viral persistence theories is that they would need to explain what is different in ME/CFS that makes this latent signaling have a deleterious effect where it doesn’t in healthy people.

Bringing it back to the topic of the thread—even if latent EBV was conclusively proven to be driving ME/CFS, antivirals wouldn’t work for latent virus, and trying to reactivate a virus in the brain in order to clear the infection carries a strong risk of brain damage.