General Survey re: Anti-virals

[heapsreal]

Some of the studies you mention are valacyclovir which is valtrex not valcyte, valgancyclovir is valcyte.


So the above study is talking about valtrex, so i would take it that valtrex and famvir would have direct killing effect of ebv??

Easy to get the generic name of valtrex and valcyte mixed up.

I may have also mixed up the post 8 previous with the last post mentioning valgancyclovir too??

 

[Butydoc]

@Butydoc, I was afraid someone would ask this, should have kept better notes!

Here are some of the articles I looked at, most from cancer journals, but the parts about the mechanisms of the antivirals are not cancer-specific. (Notice they're all about valcyte, I'm figuring the mechanism might be the same for all the antiherpes AVs, but not sure).

I accessed the articles via my University so not sure if they are available freely, happy to supply copies if you would like.

Would love your thoughts on all this as a professional!

Israel, B. F., & Kenney, S. C. (2003). Virally targeted therapies for EBV-associated malignancies. Oncogene, 22(33), 5122-5130. (review article)
The relevant bit: "Tumor cells containing the lytic (but not latent) type of EBV infection express virally encoded kinases (BGLF4 and the viral thymidine kinase) that induce phosphorylation of the prodrug, GCV, converting it to its active cytotoxic form (Moore et al., 2001). Phosphorylated GCV inhibits not only the virally encoded DNA polymerase, but also inhibits the host cell DNA polymerase and is thus cytotoxic (Tiberghien, 1994; Conners, 1995). Furthermore, phosphorylated GCV can be transferred into nearby cells, thus inducing 'bystander' killing (Freeman et al., 1993; Chen et al., 1995; Conners, 1995).

Feng, W. H., Hong, G., Delecluse, H. J., & Kenney, S. C. (2004). Lytic induction therapy for Epstein-Barr virus-positive B-cell lymphomas. Journal of virology, 78(4), 1893-1902.
The relevant bit: "EBV manifests two distinct phases in its life cycle: latency and lytic replication. During latency, EBV expresses a limited number of viral genes, which are involved in tasks such as stimulating cell proliferation, inhibiting apoptosis, blocking viral lytic replication, and assuring accurate and equal partitioning of the episomal viral genome to daughter cells (31, 43). However, during the lytic replication phase of the EBV life cycle, many more viral genes are expressed which encode proteins involved in viral DNA replication and viral particle synthesis. In addition, during the lytic form of infection, two virally encoded kinases, the EBV thymidine kinase (EBV-TK) and the BGLF4 gene product, which phosphorylate the prodrug GCV and convert it into its active cytotoxic form (11, 33, 37, 41, 53), are expressed. Phosphorylated GCV inhibits not only the virally encoded DNA polymerase but also the cellular DNA polymerase, leading to premature termination of the nascent DNA and cell death (14, 23, 34). In addition, phosphorylated GCV can be transferred to adjacent cells, thus inducing “bystander” killing (23). Lytic EBV infection also confers sensitivity to the cytotoxic effects of zidovudine (AZT), possibly by inducing AZT phosphorylation (10, 28, 41, 52). However, GCV and AZT are not generally effective for treating EBV-positive tumors because most tumor cells are infected with the latent form of EBV and therefore do not express the kinases which activate these drugs."

Young, L. S., & Rickinson, A. B. (2004). Epstein–Barr virus: 40 years on. Nature Reviews Cancer, 4(10), 757-768.
The relevant bit: “Other approaches are based on the induction of the EBV lytic cycle, either by pharmacological agents or by delivery of EBV immediate-early genes, thereby inducing virus-encoded kinases (EBV thymidine kinase and BGLF4, a protein kinase) that phosphorylate the nucleoside analogue gancyclovir to produce its active cytotoxic form”.

Hi Woolie,

Thanks for the references. It appears from these abstracts that the prodrug GCV can actually kill cells infected with EBV that are induced to be in the lytic phase. I would think for patients treated with Valcyte that develop a "Herx" type of reaction, if EBV die off is thought to be the reason, then this virus must be in the lytic phase. The problem I have with this hypothesis is that there doesn't appear to be viral particles in the blood which I would expect from the lytic phase. Lipkin was unable to find pathogens in the blood of CFS/ME patients. This makes me question the above proposed mechanism for the reaction people get from Valcyte. Still very interesting.

Best,
Gary

 

[PDXhausted]

What about something like this? Epithelial cell infection...
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2679674/

 

[Woolie]

I may have also mixed up the post 8 previous with the last post mentioning valgancyclovir too??

@heapsreal Yep. The bystander and cell killing articles were all about GCV (ganciclovir), a prodrug of valganciclovir/valcyte. But you're right: the long-term administration study of normals was about valacyclovir/valtrex.

 

[Woolie]

Hi Woolie,

Thanks for the references. It appears from these abstracts that the prodrug GCV can actually kill cells infected with EBV that are induced to be in the lytic phase. I would think for patients treated with Valcyte that develop a "Herx" type of reaction, if EBV die off is thought to be the reason, then this virus must be in the lytic phase. The problem I have with this hypothesis is that there doesn't appear to be viral particles in the blood which I would expect from the lytic phase. Lipkin was unable to find pathogens in the blood of CFS/ME patients. This makes me question the above proposed mechanism for the reaction people get from Valcyte. Still very interesting.

Best,
Gary

@Butydoc, Actually, this very problem is what triggered my reading frenzy! I was not convinced about the whole AV treatment thing, because if we're not producing active virions - no lytic phase - then how can AVs work at all, let alone produce Herx type reactions? That leaves only the anti-inflammatory account of how they work.

Then I read about that study of EBV-positive normals (above), who presumably don't have a lot of lytic activity, and it turns out valtrex IS effective at reducing their EBV loads over the long term. How can this happen? It doesn't seem sensible to suggest its due to the anti-inflammatory effects of AVs (first of all, these people aren't sick, and second of all the start and end points of the study are EBV counts, so an anti-inflammatory account is torturous at best). The best explanation I could come up with was that EBV also attempts the lytic transition from time to time even in normal people (well, it must, otherwise, how would the disease ever infect others?). The AVs operate to kill these cells, and over time, when combined with the natural life of B cells, the result is fewer latently infected cells.

So then I tried to find out more about the drug mechanism, and discovered that the proteins that trigger the antiviral action in AVs are produced at a slightly earlier stage of the latent-lytic transition process than the virions themselves (see above). This may not mean anything, but if Glaser's abortive replication hypothesis is correct, and many EBV infected cells get to the early stages of the lytic transformation - without completing it - then it could be really important to know exactly what stage of the process the AVs are effective. And it turns out its the early stage, before virions are actually produced. Glaser suggests that its the proteins produced at the IE stage, prior to the early stage, that trigger the massive immune reaction in MECFS. Okay, so maybe our immune reaction at this stage is so effective that no cell ever makes it past the IE stage to the early stage where it can be killed by AVs. But perhaps again - like the normals - a good few get through. These could be then be targetted by the AVs directly.

Sorry for long post, wanted to really set it all out. What do you think?

 

[Butydoc]

@Butydoc, Actually, this very problem is what triggered my reading frenzy! I was not convinced about the whole AV treatment thing, because if we're not producing active virions - no lytic phase - then how can AVs work at all, let alone produce Herx type reactions? That leaves only the anti-inflammatory account of how they work.

Then I read about that study of EBV-positive normals (above), who presumably don't have a lot of lytic activity, and it turns out valtrex IS effective at reducing their EBV loads over the long term. How can this happen? It doesn't seem sensible to suggest its due to the anti-inflammatory effects of AVs (first of all, these people aren't sick, and second of all the start and end points of the study are EBV counts, so an anti-inflammatory account is torturous at best). The best explanation I could come up with was that EBV also attempts the lytic transition from time to time even in normal people (well, it must, otherwise, how would the disease ever infect others?). The AVs operate to kill these cells, and over time, when combined with the natural life of B cells, the result is fewer latently infected cells.

So then I tried to find out more about the drug mechanism, and discovered that the proteins that trigger the antiviral action in AVs are produced at a slightly earlier stage of the latent-lytic transition process than the virions themselves (see above). This may not mean anything, but if Glaser's abortive replication hypothesis is correct, and many EBV infected cells get to the early stages of the lytic transformation - without completing it - then it could be really important to know exactly what stage of the process the AVs are effective. And it turns out its the early stage, before virions are actually produced. Glaser suggests that its the proteins produced at the IE stage, prior to the early stage, that trigger the massive immune reaction in MECFS. Okay, so maybe our immune reaction at this stage is so effective that no cell ever makes it past the IE stage to the early stage where it can be killed by AVs. But perhaps again - like the normals - a good few get through. These could be then be targetted by the AVs directly.

Sorry for long post, wanted to really set it all out. What do you think?

Hi Woolie,

What you present seems compelling except I still have a few problems with this hypothesis. In normal individuals treated with GCV the EBV load is reduced over time. Is this due to natural death of some B cells with the suppression of EBV replication by the antiviral or cell death caused by the phosphorylation of GCV. Not clear from the abstracts above. If cell death was caused by phosphorylation of GVC, wouldn't you expect some viral proteins and DNA segments to be released into the blood? Since no pathogens were found by Lipkin in CFS/ME patients, how then would Valcyte work. Since Lipkin only tested plasma, maybe the answer will be in the deep sequencing of the whole blood.

Best,
Gary

 

[Woolie]

Hi Gary,

In normal individuals treated with GCV the EBV load is reduced over time. Is this due to natural death of some B cells with the suppression of EBV replication by the antiviral or cell death caused by the phosphorylation of GCV. Not clear from the abstracts above.

The study of normals used valacyclovir, but that's neither here nor there... My understanding from what little reading I've done is that phosphorylation IS the mechanism by which GCV works: the cell dies, so no virions are produced. Valyacyclovir/acyclovir seems to work in the same way, but is less potent:

http://cancerres.aacrjournals.org/content/58/17/3873.full.pdf

I have so much respect for the people who designed these drugs, what a marvel! They are basically poison to cells, but only when activated by the viral TK. That is, they are incredibly selective killers. Isn't that just so elegant? I hear the guy that invented acyclovir won a Nobel prize.

If cell death was caused by phosphorylation of GVC, wouldn't you expect some viral proteins and DNA segments to be released into the blood? Since no pathogens were found by Lipkin in CFS/ME patients, how then would Valcyte work. Since Lipkin only tested plasma, maybe the answer will be in the deep sequencing of the whole blood.

Your points are really good ones. To clarify: you're saying that no AV treatment would be "perfect", effectively phosphorylating all targets, so some cells should still succeed in producing virions some of the time? And why can't we detect them? Good question!

I haven't any answer to this. I don't really know enough about where these virions might show up, and what concentration you'd need to detect them. Would they appear in the circulating blood? In the lymph? In the saliva? I'm no doctor, but the lymph would seem a good candidate. But maybe we're just fishing too hard for confirmation of the viral connection, and there's a better account out there....

I must read more about what Lipkin's doing.

Woolie

 

[Butydoc]

Hi Gary,



The study of normals used valacyclovir, but that's neither here nor there... My understanding from what little reading I've done is that phosphorylation IS the mechanism by which GCV works: the cell dies, so no virions are produced. Valyacyclovir/acyclovir seems to work in the same way, but is less potent:

http://cancerres.aacrjournals.org/content/58/17/3873.full.pdf

I have so much respect for the people who designed these drugs, what a marvel! They are basically poison to cells, but only when activated by the viral TK. That is, they are incredibly selective killers. Isn't that just so elegant? I hear the guy that invented acyclovir won a Nobel prize.



Your points are really good ones. To clarify: you're saying that no AV treatment would be "perfect", effectively phosphorylating all targets, so some cells should still succeed in producing virions some of the time? And why can't we detect them? Good question!

I haven't any answer to this. I don't really know enough about where these virions might show up, and what concentration you'd need to detect them. Would they appear in the circulating blood? In the lymph? In the saliva? I'm no doctor, but the lymph would seem a good candidate. But maybe we're just fishing too hard for confirmation of the viral connection, and there's a better account out there....

I must read more about what Lipkin's doing.

Woolie

Hi Woolie,

Actually I thought most antivirals work by preventing replication, not by cell lysis. Since GCV inhibits viral and host DNA polymerases, there must be viral DNA in the cell. When the cell lysis, it should release some fragments of the viral DNA. Using PCR, I would think the viral DNA would be multiplied many times so that detection can me made. I don't believe whole virons are necessary.

Best,
Gary

 

[Woolie]

@Butydoc , I think I get what you say about fragments of viral DNA being potentially detectible, even if they are not sufficiently complete to infect new cells.

Is that what you mean by "preventing replication"? The viral DNA fragments are no longer viable? And when you say you take it most AVs don't work "by cell lysis", do you mean, by killing the host cell? Or something else?

Perhaps because I've been reading articles focused on AVs as a cancer treatment, they simply emphasise the cytotoxic aspect and ignore the replication prevention bit?

Thanks, btw, for all your posts, I promise this one will be my last!

 

[Woolie]

@Woolie Thank you for doing all this research and sharing it with us. I am so curious to hear what @Butydoc thinks of it and everyone else with strong science backgrounds. I am now wondering if Valcyte would have been a better choice for me than Famvir but I just don't think I would have tolerated it and would have gotten all the dangerous side effects (as I always do.)

I think no question, whatever these AVs do, valcyte is probably more effective at it than valtrex/famvir. But then there's the drawbacks: cos its so dangerous, people can't take it for as long a period as those others, that might be a huge drawback if many of us need sustained, long-term treatment to show effects. Maybe a good strategy would be to do the shorter bursts of valcyte - doctor permitting - and "drop back" to one of the others during the down time.

For me, the problem with valcyte is convincing my doc the risks are worth it (he's rightfully concerned!) and the cost, as I'm self funding..... but then, people seem to take lower daily doses, so maybe not that much more expensive in the long run?

 

[Woolie]

What about something like this? Epithelial cell infection...
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2679674/

Gosh, @PDXhausted, interesting article! On another post about rituximab, Jonathan Edwards has pointed out that the benefit of rituximab is in MECFS is still often time limited, which he believes undermines an EBV eradication account of the effect.

This article suggests depleting the B cells isn't enough to eradicate latent EBV infection, which persists in other cells. If some or many of our problems stem from EBV latent infection (a big if), then it would seem that the problem is more than just having a high viral load... even if we get that load down, it still probably bounces back quickly. It looks more like our immune systems simply cannot contain this infection for some reason.... puts the heat back on immune system explanation...

 

[heapsreal]

@Woolie is there any research showing valcyte actively kills other herpes viruses cmv/hhv6??

 

[Woolie]

@Woolie is there any research showing valcyte actively kills other herpes viruses cmv/hhv6??

Good question, @heapsreal, but I can;t answer because I haven't read anything on this - yet. People are super interested in EBV because of its documented role in several cancers, so there's lots more stuff on this. I'm super interested in EBV because of its connection to B cells (I understand it is the only member of the herpes family that makes substantial use of these cells). Since many of us have relapses when we battle a new infection - something that activates and stresses B cells amongst others - it seems to me an especially worthy candidate for our attention.

But as I understand it, all the antiherpes AVs work via the same basic mechanism, and are effective - to greater or lesser degrees - on all members of the herpes family. Some appear to "fit" better with some herpes viruses than others, but its all a question of degree.

I'm keen to hear what Gary has to say about all this - it may be that the stuff I've read has focused on the cell-killing properties of these AVs, and the authors simply have no interest in their other possible benefit - preventing new cells from being infected (this is not so important to cancer researchers).

 

[Woolie]

@Butydoc, not sure if you got this tag, as I accidentally tagged "Gary" the first time. Would love to hear you thoughts on these questions, if you have time.

I think I get what you say about fragments of viral DNA being potentially detectible, even if they are not sufficiently complete to infect new cells.

Is that what you mean by "preventing replication"? The viral DNA fragments are no longer viable? And when you say you take it most AVs don't work "by cell lysis", do you mean, by killing the host cell? Or something else?

Perhaps because I've been reading articles focused on AVs as a cancer treatment, they simply emphasise the cytotoxic aspect and ignore the replication prevention bit?

Thanks, btw, for all your posts, I promise this one will be my last!

 

[heapsreal]

@Woolie i think the subject of substances actually killing viruses either in active or latent states is interesting and important for cfs/me. It would be great if you could continue to share what you find researching, sometimes others either dont have the time or energy to do it ourselves, but if your on a roll with researching the subject, keep pumping it out as im sure many are interested.

I think you mentioned cycling between valcyte and famvir/valtrex. This sounds like a good idea. Valcyte to potentially kill viral infected cells eg for a 2 week duration and then switch to say famvir to stop replication while off valcyte. These can make antiviral treatment more affordable but also may reduce side effects. This is something im looking into. I have even thought if combining valtrex and famvir together would have a 1 + 1 = 3 maybe??

I think if at the same time we can raise interferon levels which can help increase nk function can also be an added benefit to help treat viruses. Not to different to hepatitis using the antiviral ribavirin with interferon treatment. This has been shown to irradicate the virus in some.

 

[Gingergrrl]

Thanks, btw, for all your posts, I promise this one will be my last!

@Woolie I hope you will keep posting anything that you find and it has all been really interesting and helpful (even though I don't understand most of it!) If you happen to come across anything re: Famvir and EBV or other herpes viruses please post it!

 

[Butydoc]

@Butydoc, not sure if you got this tag, as I accidentally tagged "Gary" the first time. Would love to hear you thoughts on these questions, if you have time.

I think I get what you say about fragments of viral DNA being potentially detectible, even if they are not sufficiently complete to infect new cells.

Is that what you mean by "preventing replication"? The viral DNA fragments are no longer viable? And when you say you take it most AVs don't work "by cell lysis", do you mean, by killing the host cell? Or something else?

Perhaps because I've been reading articles focused on AVs as a cancer treatment, they simply emphasise the cytotoxic aspect and ignore the replication prevention bit?

Thanks, btw, for all your posts, I promise this one will be my last!

Hi Woolie,

My understanding concerning nucleoside type antiviral drugs is that they inhibit replication of viral DNA by incorporating these analogs into the viral DNA causing the termination of that sequence. It appears that these type of antiviral drugs are all phosphorylated prior to incorporation. Since the DNA sequences aren't complete, there wouldn't be any viral proteins produced, hence no virons are produced. If the cells were lysed as suggested by the articles you referenced, I would think one would see some viral paricles released into the plasma. There must be viral particles in the cells in order for the antivirals to work if the proposed benefits to treated CFS/ME is thought to be from their antiviral mechanism.

Lipkin was trying to find pathogens in patients plasma with CFS/ME. No pathogens were found. This is the reason why i'm starting to believe that Valcyte may benefit some people with CFS/ME by it's ability to suppress microglial cells rather than as an antiviral drug. I'm not sure why Lipkin used plasma rather than whole blood in his experiments, maybe whole blood would have yielded a different result.

I'm not sure why people with CFS/ME sometimes develop an abnormal response to Valcyte. Some have referred to this response as a "Herx" type of reaction. During the initial experiments with Valcyte, Montoya felt that this "Herx" reaction was a positive indicator of likely success. He has since changed his mind. I personally don't believe that cell death is the cause of this reaction. People report this type of reaction with many different types of treatment modalities. Supplements, antibiotics, antivirals are reported by many CFS/ME sufferers to cause this type of reaction. Many more questions than answers.

Best,
Gary

 

[Woolie]

Thanks, @Butydoc! Your explanation was really helpful. I promised not to ask any more questions after this, so I'll be true to my word!

It seems there are many mysteries and paradoxes in the study of ME. For those of us whose illness onset was a severe viral illness - and prior to that, robust good health - we need a way of understanding how the triggering virus led to the illness we now suffer, and if it no longer plays a role, what sustains and maintains the abnormal patterns. It would seem to me that a purely immune hyperreactivity account would predict a slow dimunition in the severity of symptoms over time. But something sustains it, and in some cases exaggerates it (in my case, in a relapsing-remitting kind of way). What could that be?

I think a lot about ME is mysterious, but one advantage we have is clear etiology. We have good evidence that in a large number of cases, the illness is very likely caused by a viral infection. So many systemic illnesses have a confusing and bewildering set of causal factors, so in this way, ME has an edge that we need to make use of. I know it doesn't apply to everyone, but its a way in that might give us insights that can be extended to other cases too.

 

[heapsreal]

Lipkin was trying to find pathogens in patients plasma with CFS/ME. No pathogens were found.

I never understood how he never found any pathogens. Its said that 90% plus of adults have had or carry ebv/cmv/hhv6, or is it these pathogens are elsewhere but not in the plasma eg ebv in B cells, or cmv in salivary glands and lymphatic system or hhv6 in the nervous system especially the intergrated hhv6 which dr peterson mentions frequently?

Do we know if patients who are put on valcyte for organ transplant as a preventative , experience any type of reaction at the start of treatment which would be similar to a die off type reaction cfs people get. Does this also occur in HIV patients?

 

[Butydoc]

Thanks, @Butydoc! Your explanation was really helpful. I promised not to ask any more questions after this, so I'll be true to my word!

It seems there are many mysteries and paradoxes in the study of ME. For those of us whose illness onset was a severe viral illness - and prior to that, robust good health - we need a way of understanding how the triggering virus led to the illness we now suffer, and if it no longer plays a role, what sustains and maintains the abnormal patterns. It would seem to me that a purely immune hyperreactivity account would predict a slow dimunition in the severity of symptoms over time. But something sustains it, and in some cases exaggerates it (in my case, in a relapsing-remitting kind of way). What could that be?

I think a lot about ME is mysterious, but one advantage we have is clear etiology. We have good evidence that in a large number of cases, the illness is very likely caused by a viral infection. So many systemic illnesses have a confusing and bewildering set of causal factors, so in this way, ME has an edge that we need to make use of. I know it doesn't apply to everyone, but its a way in that might give us insights that can be extended to other cases too.

Hi Woolie and Heapsreal

My illness also started out with an acute viral upper respiratory infection. I developed CFS/ME at the age of 50, my brother developed the syndrome at age 20, mother developed Takayasu arteritis, an autoimmune disease at age 78 and my older brother died from MS at age 61. I find it difficult to believe all of my family developed these immune dysfunction syndromes as a result of an on going infection. It seems more plausible to me that my family has a genetic defect that predisposes us to develop these syndromes which may be precipitated by an acute infection or another stressor.

I don't know if other diseases like HIV have a "HERX" type of reaction from antivirals. My wife gets shingle outbreaks and responds well to acyclovir without any negative reaction while if I take the same dose of acyclovir, I get a substantial "HERX" type of reaction. There must be something else other than die off responsible for this type of reaction in CFS/ME patients.

Best,
Gary