Nivolumab greatly reduces HIV reservoirs in a patient: Could it work for ME/CFS viruses?

[Hip]

Anti-HIV Effect of Nivolumab: One Possible Mechanism is Via Reversing T-Cell Exhaustion

An HIV patient treated with the anti-cancer drug nivolumab had in a major decrease in his HIV reservoirs (these viral reservoirs normally persist in spite of antiretroviral therapy).

Article: Cancer drug leads to 'drastic decrease' in HIV infection in lung cancer patient

Study: Drastic decrease of the HIV reservoir in a patient treated with nivolumab for lung cancer

Nivolumab is a PD-1 inhibitor. PD-1 is also called CD279. See programmed death-1 protein.

The function of PD-1 is to down-regulate the immune response, thereby promoting self-tolerance by suppressing T-cell inflammatory activity. So the activation of PD-1 helps prevent autoimmune diseases, but it can also prevent the immune system from destroying cancer cells, and clearing viral infection.

Nivolumab blocks PD-1 activation, and thereby increases the immune response to cancers. Other PD-1 inhibitors include pembrolizumab.

In the above study, the authors hypothesize that PD-1 inhibitors like nivolumab may target HIV in two ways: (1) by restoring immune function in exhausted T-cells that express the PD-1 receptor, and (2) by promoting HIV gene transcription in the reservoirs.

For ME/CFS purposes, it is the reversal of T-cell exhaustion that might conceivably help clear the chronic enterovirus and herpesvirus infections associated with ME/CFS.

This paper found evidence for CD8 T-cell exhaustion in ME/CFS patients.



PD-1, T-Cell Exhaustion and the Antiviral Response

This paper provides an overview of T-cell exhaustion:

• Persistent viral infections can result in the exhaustion of antiviral T-cells.
• Excessive and sustained levels of viral antigen drive T-cell exhaustion.
• Exhausted T-cells are distinct from typical effector and memory subsets.
• Exhausted T-cells are functionally ineffective and compromise viral clearance.
• Blocking inhibitory receptors and modifying cytokine levels can alleviate exhaustion.

This paper says high antigen levels are the cause of T-cell exhaustion in chronic viral infection.

This paper says that sustained expression of the PD-1 receptor on T-cells is a characteristic marker of T-cell exhaustion. Although recent data show that PD-1 is not required for initiating T-cell exhaustion, and that absence of PD-1 even promotes accumulation of exhausted CD8+ T cells in mice.

This paper says that T-cell exhaustion due to persistent antigen stimulation is a key feature of chronic viral infections and cancer. PD-1 is a major regulator of T-cell exhaustion, and blocking the PD-1 pathway restores T-cell function and improves pathogen control and tumor eradication.



Could Nivolumab be Effective for Chronic Enterovirus Infection in ME/CFS?

ME/CFS is linked to chronic non-cytolytic enterovirus infections that reside inside cells. Could nivolumab help clear chronic enterovirus?

This study on acute coxsackievirus B3 myocarditis found PD-1 expression was markedly increased in heart myocytes, and that blocking PD-1 increased the myocardial inflammation. The authors suggest that activating PD-1 or PD-L1 will be useful for suppressing myocardial inflammation and myocardial damage in acute infections.

But in ME/CFS, the acute stage of the infection has passed, and we are likely dealing with chronic infections, and in the case of enterovirus-associated ME/CFS, chronic non-cytolytic infections. Could blocking PD-1 with nivolumab help clear these chronic enterovirus infections?


In the case of Epstein-Barr virus and cytomegalovirus associated ME/CFS, this study found no difference in the expression of the T-cell exhaustion marker PD-1 on EBV- and CMV-specific T-cells between patients and controls.



Side Effects of Nivolumab

This paper says adverse effects of anti-PD-1 immunotherapy treatment like nivolumab include the precipitation of diabetes (one case of diabetes was reported in 206 subjects treated with nivolumab). Conceivably the risk might be high in patients with coxsackievirus B1 or coxsackievirus B4 infections, as these viruses are linked to type 1 diabetes (these viruses can infect the insulin-producing beta cells of the pancreas).

 

[Learner1]

Very interesting.

My ME/CFS developed after surgery and chemotherapy for stage 3 cancer, which is now gone. My oncologist has been puzzled by the fact that I don't fit the profile for my cancer, but was quite intrigued by the letter he received from my immunologist describing my immune system problems.

My ME/CFS doctor suspects my immune system issues predated my cancer, through its hard to tell. I've suspected that all my health problems are related, including several chronic infections, though no Enteroviruses.

I'm a bit thick headed today to try to sift through all of this, but how would one determine if one's T cells were exhausted?

And then, if they were, the Nivolumab would fix them and make the viruses (and cancer) go away?

Then, how would all of this relate to B cell antibodies some of us have?

 

[Hip]

I'm a bit thick headed today to try to sift through all of this, but how would one determine if one's T cells were exhausted?

Unfortunately I don't know that much about T-cell exhaustion, nor about PD-1. I just saw the HIV paper, and quickly put this thread together. @halcyon is interested in T-cell exhaustion, and may be able to answer your questions.

 

[Learner1]

Thank you for bringing the info together... I'll look forward to any input from @halcyon

 

[frederic83]

It says here (in french) that it's just one case and that in a conference on HIV in Paris, there were three talks about this strategy and all three said it failed. The conclusion is that it might be useful if used in a broader strategy (for HIV).

 

[halcyon]

In the case of Epstein-Barr virus and cytomegalovirus associated ME/CFS, this study found no difference in the expression of the T-cell exhaustion marker PD-1 on EBV- and CMV-specific T-cells between patients and controls.

This was an important study because it blows a hole in the idea that these viruses cause CFS. Chronic EBV infections are known to cause high PD-1 expression as you would expect.

but how would one determine if one's T cells were exhausted?

There are a number of cell surface markers that are associated with T cell exhaustion, including PD-1. The problem is that I don't think any testing for this is commercially available at this point. Exhausted T cells put out less TNF-a, IFN gamma, and IL-2, so possibly measuring these cytokines might show something but it might not make enough of a dent in global serum cytokine levels to be measurable.

In general I don't think PD-1 blockade will be a safe treatment for ME given the nasty immunopathology side effects mentioned. But I do think T cell exhaustion is a critical part of the disease and perhaps it can be approached from other directions such as recombinant cytokine treatment with IL-7 or IL-21 or blockade of things like IL-10, TGF beta, etc.

 

[Learner1]

This was an important study because it blows a hole in the idea that these viruses cause CFS. Chronic EBV infections are known to cause high PD-1 expression as you would expect

Not sure that's what it concluded...this is what it says:

Taken together, our study provides clear evidence that deficiency of EBV-specific immune response is present in CFS. As EBV is known to be controlled by cell-mediated immunity, a diminished memory T- and B-cell response may result in impaired control of EBV. EBV replication is risk factor for development of lymphomas and autoimmune diseases both occurring at enhanced frequencies in CFS patients

It is diminished T and B cell response and impaired control of EBV.

My ME/CFS doctor said he'd never seen anyone with labs like mine - no EBNA or EA, but very high VCA and PCR. He thinks EBV is behind my autoimmune antibodies and current situation.

What I am not sure of is how it played into my cancer, if at all.

I'll ask about recombinant cytokine treatment. Thank you.

 

[halcyon]

Not sure that's what it concluded...this is what it says:

According to this paper:

High amounts of PD-1 are expressed on EBV-specific CD8+ T cells during chronic infection

This is inconsistent with the Loebel findings which showed no change in PD-1 expression which is a sign that EBV is not highly active in CFS patients. Loebel found that early replication stages were not as well controlled, but the intermediate replication gene BZLF-1 was not expressed which I take to mean the virus is undergoing latent replication but not full reactivation.

 

[Hip]

This is inconsistent with the Loebel findings which showed no change in PD-1 expression which is a sign that EBV is not highly active in CFS patients. Loebel found that early replication stages were not as well controlled, but the intermediate replication gene BZLF-1 was not expressed which I take to mean the virus is undergoing latent replication but not full reactivation.

Have you come across Dr Martin Lerner's abortive infection theory of ME/CFS, @halcyon?

I only recently got to grips with Lerner's theory. Dr Lerner proposed that in the herpesvirus subset of ME/CFS, patients may be suffering from a chronic abortive herpesvirus infection.

An abortive infection is not the same as a latent infection. An abortive infection is an ongoing infection in cells, but one which does not and cannot produce any new viral particles. In this way, abortive infection is very similar to a enterovirus non-cytolytic infection, which also is ongoing in cells, but does not manufacture new viral particles.

By contrast, in latent infection, there is no ongoing infection in the cell, because the virus normally lies dormant in the cell (although in some circumstances it can partially reawaken while still being in the latent state). But when a latent virus in a cell does fully reawaken, it is perfectly able to start producing new viral particles. So this is the difference between latent infection and abortive infection. In summary:

Latent infection = dormant infection that can reawaken to produce viral particles.
Abortive infection = ongoing active infection that cannot under any circumstances produce viral particles.


So non-cytolytic and abortive infections may explain why in ME/CFS, antibody titers are often high, but when you perform a PCR blood test on the patient, the result is often negative: it is negative because non-cytolytic and abortive infections don't produce any viral particles, so therefore you don't find much virus in the blood by PCR.

Whereas when you perform PCR on the muscle tissues of ME/CFS patients, then you do often find evidence of chronic infection, because the infection is ongoing in the muscle tissues.


Unfortunately there is as yet little evidence for herpesvirus abortive infection in ME/CFS. However, there is as we know good evidence for ME/CFS patients having non-cytolytic enterovirus infections. Non-cytolytic infection in ME/CFS has reasonable empirical evidence base behind it.

But nevertheless, in spite of the current lack of empirical evidence, I find the abortive herpesvirus infection theory of ME/CFS very attractive, because this theory may help unify the enterovirus subset and the herpesvirus subset of ME/CFS into one framework of understanding: the understanding that both subsets are caused by a chronic viral infection in the cells that is active and ongoing, but produces no new viral particles. So these are not the standard type of active viral infection; they are rather unusual in that they are chronic but don't manufacture viral particles, thus the blood is mostly free of virus in ME/CFS.


In some of the early British research on enteroviruses is ME/CFS, they found enterovirus RNA in the muscle biopsy tissue samples of ME/CFS patients, but they also found EBV DNA in these muscle tissues. See this 1991 study. So perhaps that EBV DNA was due to an EBV abortive infection in the muscles.

 

[Learner1]

Still following along here, as I had EBV DNA in my blood, which seems to have snowballed into autoimmunity and my ME/CFS.

How does one get an EBV PCR muscle test? Is it research only, or is there some lab that accepts a biopsy?

And is this the kind of recombinant cytokine treatment you mentioned? Who delivers such a treatment?

 

[halcyon]

As I've seen elsewhere, and as that paper notes, EBV only has known tropism for B lymphocytes and epithelial cells. I don't think infection of these cells is enough to explain the symptoms of ME, whereas infection of CNS, muscles, and organs would seem to be required to cause symptoms of ME. As the paper notes, the EBV in muscle could have been due to infiltrating B cells. It is interesting that the EBV and enterovirus positive patients don't overlap, which matches other studies. I do think it's possible that there is a subset of people that have an EBV caused CFS-like syndrome, but I don't think this is the same as ME and neither did Ramsay, Dowsett, or Mowbray.

 

[Hip]

I do think it's possible that there is a subset of people that have an EBV caused CFS-like syndrome, but I don't think this is the same as ME and neither did Ramsay, Dowsett, or Mowbray.

There certainly seems to be a good recovery rate in mononucleosis-triggered ME/CFS: this longitudinal study I was looking at recently found that in a group of mono-triggered ME/CFS patients, only 10% were working to start with (part-time or full-time), but after an average of 7 years, 55% of them were back to work.

I don't think the recovery rate for enterovirus-associated ME/CFS is anything like as good, although there have been no enterovirus-specific recovery studies I am aware of. However, general ME/CFS recovery rate studies show that recovery is uncommon.


But for me, if, as well as enterovirus, EBV and other viruses can also trigger ME/CFS, then we need to find a theory that can encompass all of these viruses, and provide a mechanism explaining how they lead to ME/CFS. That is, if we want to keep the viral theory of ME/CFS alive. So it occurred to me that the non-cytolytic / abortive infection idea could be such a theory that encompasses all the ME/CFS-associated viruses.

How does one get an EBV PCR muscle test? Is it research only, or is there some lab that accepts a biopsy?

And is this the kind of recombinant cytokine treatment you mentioned? Who delivers such a treatment?

I don't think any ME/CFS specialists use muscle biopsies outside of research environments, in part because they are painful and leave a scar. Dr John Chia's innovation is to take stomach tissue biopsies instead, and test those for enterovirus, as these are not painful. He routinely tests his patients this way for enterovirus.

Not sure what you are referring to regarding a "recombinant cytokine treatment"

 

[Learner1]

I don't think any ME/CFS specialists use muscle biopsies outside of research environments, in part because they are painful and leave a scar. Dr John Chia's innovation is to take stomach tissue biopsies instead, and test those for enterovirus, as these are not painful. He routinely tests his patients this way for enterovirus.

The muscle biopsy does seem rather inconvenient... But how else do you know if you've gotten rid of the virus (as much as one can)?

The researchers seem to be agreeing there are subsets. The IOM, Fukuda, and CC criteria are based on symptoms, which unfortunately may emanate from a variety of sources.

But for me, if, as well as enterovirus, EBV and other viruses can also trigger ME/CFS, then we need to find a theory that can encompass all of these viruses, and provide a mechanism explaining how they lead to ME/CFS. So it occurred to me that the non-cytolytic / abortive infection idea could be such a theory that encompasses all the ME/CFS-associated viruses.

It seems there are more shades of gray here than just regular, abortive, or latent. There's also the deficient situation referred to in the article @halcyon posted. And, can fungi or bacterial infections lead to ME/CFS, too? (They seem to...)

Something definitely seems to be broken in the immune system's reaction to these viruses. And figuring what got broken/altered and fixing it, along with the collateral damage might lead to a cure.

Not sure what you are referring to regarding a "recombinant cytokine treatment"

@halcyon suggested the recombinant treatment for the exhausted T cells.

But I do think T cell exhaustion is a critical part of the disease and perhaps it can be approached from other directions such as recombinant cytokine treatment with IL-7 or IL-21 or blockade of things like IL-10, TGF beta, etc.

I was just questioning how one might be able to figure out if one might need, then track down how one might get these treatments...

 

[Hip]

It seems there are more shades of gray here than just regular, abortive, or latent.

What do you mean by shades of gray here?

Something definitely seems to be broken in the immune system's reaction to these viruses.

That's certainly a possibility, and the idea suggested in this thread is that bovine leukemia virus might be worth investigating as a possible cause of weakened immunity.

Though note that chronic non-cytolytic enterovirus infections are not just found in ME/CFS, but also coxsackievirus B myocarditis. So if there is an immune weakness, it may also feature in CVB myocarditis.

But it may just be that non-cytolytic and abortive infections are hard to get rid of once they are set up.

One possibility is that non-cytolytic and abortive infections might be created when you catch a viral infection during a time of weakened immunity, for example, stress-related immune weakness. That then may allow the virus to infect cells it would not normally have the opportunity to infect, and it occurred to me that that could be how non-cytolytic and abortive infections are created. Once created, they may be difficult to get rid of. So it could be something along those lines. That theory certainly falls in line with Dr Chia's discovery that giving steroids during acute infection increases the risk of ME/CFS.

And, can fungi or bacterial infections lead to ME/CFS, too?

Chlamydia pneumoniae can cause ME/CFS; that is an intracellular bacterium. I don't think any fungi can cause ME/CFS.

A most interesting cause of ME/CFS is parvovirus B19 infection. This is interesting because in parvovirus B19 ME/CFS there is viremia (the presence of virus in the blood), which you don't really get with enterovirus or herpesvirus ME/CFS.

So with parvovirus B19 there is an obvious cause of the symptoms, which is the ongoing viral infection. But with enterovirus and herpesvirus you don't really see such viremia, and so there is no obvious cause, which is why in enterovirus- and herpesvirus-associated ME/CFS, people always question whether these viruses are the cause, and whether there really is any ongoing infection of enterovirus or herpesvirus.

But with enterovirus-associated ME/CFS, there is evidence of an infection in the tissues, which may be the hidden cause. And likewise, in herpesvirus-associated ME/CFS, an abortive infection in the tissues may be the hidden cause, though there is not really much supportive evidence for the abortive theory.

 

[frederic83]

As I've seen elsewhere, and as that paper notes, EBV only has known tropism for B lymphocytes and epithelial cells. I don't think infection of these cells is enough to explain the symptoms of ME, whereas infection of CNS, muscles, and organs would seem to be required to cause symptoms of ME

Epithelial cells are found in most organs. EBV can infected various organs. Can it be problematic, that's another question.

 

[Hip]

I just found this new research from 2015 which proved that EBV can infect neuron cells in culture. When EBV infects neurons, it appears to create a productive infection which produces new viral particles. By contrast, when EBV infects B-cells, it creates a latent infection.

 

[frederic83]

I'm reading here, sorry it is in french, that there are three types of infections. Productive (viral particles production), abortive (no viral particles) and persistent (no viral particles). The difference between abortive and persistent is that in the latter, the behavior of the infected cell changes and possibly can cause a disease like cancer.

I'm not sure which category a latent infection would be. Either abortive or persistent, I guess.
In the CFS theory, that would probably be a persistent infection and not an abortive infection, so.

 

[Hip]

I have not seen that "persistent" terminology used in English, where "persistent" usually just means a similar thing to "chronic". Chronic and persistent infections are just ones that carry on after the initial acute infection has passed.

From Vincent Racaniello's virology blog:

In contrast to acute viral infections, persistent infections last for long periods, and occur when the primary infection is not cleared by the adaptive immune response. Varicella-zoster virus, measles virus, HIV-1, and human cytomegalovirus are examples of viruses that cause typical persistent infections. A chronic infection is a type of persistent infection that is eventually cleared, while latent or slow infections last the life of the host.

So in terms of timescale:

Acute = an infection lasting a short time (days or weeks).

Chronic = an infection lasting longer (months, years or decades).

Persistent = an infection lasting for the lifetime of the animal (never cleared from the body).



And in terms of the nature of the infection:

Productive = an infection which produces viral particles.

Latent = an infection which has purposely stopped producing viral particle, and has gone into a dormant mode inside a cell. Inside the cell, the latent virus will store its genetic code either in episomes, or via chromosomal integration. The virus can reawaken from latency a start producing viral particles again in future (this is often done during times of immune weakness, when the virus senses it is a good to reawaken).

Abortive = an infection which is ongoing (not dormant), but which is never able to produce viral particles, because the virus has entered a type of cell which does not possess the machinery necessary for the virus to replicate. So the virus is constantly trying to replicate, but never succeeds in doing so. Details of Dr Martin Lerner's abortive herpesvirus infection theory of ME/CFS here.

Non-cytolytic = an infection in which the virus has changed form: in non-cytolytic infections the virus no longer exists as a particle, but exists as strands of naked dsRNA that reside inside cells on a long term basis. Non-cytolytic infections do not produce viral particles, but they can replicate themselves inside a cell, and they may be able to spread to nearby cells (it is not certain if they can spread to other cells, but this research proposes that non-cytolytic dsDNA might spread by cellular protrusions). Non-cytolytic infections are also called: non-cytopathic and defective infections.



Enteroviruses such as coxsackievirus B and echovirus are known to produce non-cytolytic infections, and dengue virus is known to create non-cytolytic infections also.

In the tissues of ME/CFS patients infected with enterovirus, often no viral particles can be found (virus cannot be cultured from patient tissue sample), but non-cytolytic infection is found in the tissues, suggesting non-cytolytic infection, rather than a regular enterovirus infection producing viral particles, plays a fundamental role in enterovirus-associated ME/CFS.

But intriguingly, evidence for Epstein-Barr virus non-cytolytic infection has been found (see this study, which found defective EBV). So conceivably in EBV-associated ME/CFS, non-cytolytic EBV might be involved in ME/CFS etiology.