Persistent Viral Infections & New Interferon Studies

[Gemini]

Treatments that block interferon signaling may help control persistent viral infections.

Interferon is the body's major first line of defense against viral infection. Paradoxically, interferon signaling surpresses the immune system in ways that promote persistent infection.

Keep an eye on this as interferon has interested ME/CFS researchers for over 20 years, Ampligen is an interferon inducer, & Klimas/Broderick are currently looking at it among other things...

Two high-profile animal model studies in Science 12 April 2013 involving numerous NIH grants:

Persistent LCMV infection is controlled by blockade of type I interferon signaling
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA , USA.

During persistent viral infections, chronic immune activation, negative immune regulator expression, an elevated interferon signature, and lymphoid tissue destruction correlate with disease progression. We demonstrated that blockade of type I interferon (IFN-I) signaling using an IFN-I receptor neutralizing antibody reduced immune system activation, decreased expression of negative immune regulatory molecules, and restored lymphoid architecture in mice persistently infected with lymphocytic choriomeningitis virus. IFN-I blockade before and after establishment of persistent virus infection resulted in enhanced virus clearance and was CD4 T cell-dependent. Hence, we demonstrate a direct causal link between IFN-I signaling, immune activation, negative immune regulator expression, lymphoid tissue disorganization, and virus persistence. Our results suggest that therapies targeting IFN-I may help control persistent virus infections.


Blockade of chronic type I interferon signaling to control persistent LCMV infection.
Department of Microbiology, Immunology and Molecular Genetics and the UCLA AIDS Institute, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA , USA.

Type I interferons (IFN-I) are critical for antiviral immunity; however, chronic IFN-I signaling is associated with hyperimmune activation and disease progression in persistent infections. We demonstrated in mice that blockade of IFN-I signaling diminished chronic immune activation and immune suppression, restored lymphoid tissue architecture, and increased immune parameters associated with control of virus replication, ultimately facilitating clearance of the persistent infection. The accelerated control of persistent infection induced by blocking IFN-I signaling required CD4 T cells and was associated with enhanced IFN-γ production. Thus, we demonstrated that interfering with chronic IFN-I signaling during persistent infection redirects the immune environment to enable control of infection.

 

[Hip]

Interesting that in previous ME/CFS experimental research, they boosted interferon. As you mentioned, Ampligen boosts interferon, and Dr John Chia was able to bring ME/CFS into almost full remission (albeit for only a few months) using intravenous infusions of interferon.

But in these new studies, they are blocking the action of interferon, not boosting it, and then finding that by blocking interferon, other aspects of the immune system are restored, and once restored, act to clear the virus.

Certainly very interesting.

I would like to know if this approach only applies to lymphocytic choriomeningitis virus (LCMV), or whether it is applicable to other viruses, like the enteroviruses linked to ME/CFS.

 

[lansbergen]

The accelerated control of persistent infection induced by blocking IFN-I signaling required CD4 T cells and was associated with enhanced IFN-γ production.

Interferon gamma could be a clue

I think levamisole increasing interferon gamma is one of the factors that helped my improvement.

 

[heapsreal]

my undrstanding is alpha and beta interferon are anti-inflammatory where gama interferon is pro inflammatory. Im not familiar with the other interferons.

other interferon inducers are cycloferon and immunovir, there is more mostly made in eastern block countries where they are mostly used. cycloferon from what i have read only inducers alpha and beta interferon. My personal experience is that i have found cycloferon more feelable results as in felt better then with immunovir. cycloferon did greatly increase my nk function but didnt have any effect on bright nk cell function(abnormality found in recent cfs studies), i was only able to get those tests for a short time. immunovir did increase my nk numbers slightly but dont know if it increased nk function. As for both of them the feeling better from them only lasted a few weeks, maybe from anti-inflammatory effects, long term may have helped clear infections but nothing obviously noticeable long term. Maybe there a rapid tolerance issue with interferon inducers??

Also i have read that herpes virus avoid the immune system by being able to turn down interferon production. the above studies abviously show how complicated interferons are with many different types. when researching info and see the word interferon, it sparks my interest as i think its a clue to the immune dysfunction in cfs and probably ties in with nk function.

thanks for posting that study.
cheers!!

 

[Gemini]

I would like to know if this approach only applies to lymphocytic choriomeningitis virus (LCMV), or whether it is applicable to other viruses, like the enteroviruses linked to ME/CFS.

Hip,

Great question! Glad you mentioned enteroviruses, Dr. Chia is in So. Calif. geographically close to these researchers.

Besides LCMV, studies mention hepatitis C, HIV, & SIV then generalize to "persistent viral infections."

I find the HCV treatment observation below interesting & hope Ampligen's sponsor, FDA, and patients who want to know why that drug works in some but not all patients follow this research as it goes forward (excerpts):

UCLA study conclusion:
Our results demonstrate that chronic IFN-I signaling during persistent infection drives the immunosuppressive program and that interfering with IFN-I signaling restores multiple parameters of productive immunity, allowing for viral clearance. IFN-I treatment in combination with the antiviral drug ribavirin is often effective at eradicating HCV infection. However, some patients fail to have a sustained virologic response. A characteristic of patients that fail IFN-I/ribavirin therapy is a heightened IFN-I signature before treatment that fails to substantially increase with therapy (25, 26). Thus, the initially high IFN-I signature may lead to enhanced immune dysfunction, and consequently adding more IFN-I is ineffective. These results highlight the duality of IFN-I during viral infection: Acute IFN-I signals possess antiviral and immune stimulatory potential required for clearance of infection, but when virus cannot be controlled, acutely sustained IFN-I signaling induces immunosuppression that facilitates persistent virus infection. Considering that HIV and HCV infections are also associated with immune activation driven by chronic IFN-I signaling (23, 27–29), a similar blockade of IFN-I may improve control of these infections. In total, our data support IFN-I as a central rheostat and regulator of the immunosuppressive program and the possibility that it may be feasible to redirect entire immunologic programs by modulating activity of a single pathway: IFN-I.

Scripps study conclusion:
Chronic immune activation after HIV infection is documented, and suppression of this hyperactivated state may alleviate pathologies associated with HIV infection (7). Disease after experimental simian immunodeficiency virus (SIV) infection in rhesus macaques correlates with elevated IFN-I and inflammatory signatures (30, 31). In contrast, SIV infection in sooty mangabeys and African green monkeys, which develop modest pathology despite similar viral loads as macaques, correlates with reduced IFN-I and inflammatory signatures (32). Similar correlations with respect to reduced immune activation exist in HIV-infected elite controllers, although whether reduced immune activation follows better control of virus infection is debatable (33, 34). Moreover, an elevated interferon signature is observed in HCV-infected patients despite limited control of virus replication and development of liver pathology (35, 36). Thus, the IFN-I signaling pathway may be a viable target to control persistent viral infections.

 

[Gemini]

Also i have read that herpes virus avoid the immune system by being able to turn down interferon production. the above studies abviously show how complicated interferons are with many different types. when researching info and see the word interferon, it sparks my interest as i think its a clue to the immune dysfunction in cfs and probably ties in with nk function.

thanks for posting that study.
cheers!!

 

[Gemini]

heapsreal,

Seems Interferon is a hot topic these two studies drawing over a dozen NIH grants if I counted right!

Besides publishing the studies Science included an article "An Interferon Paradox" summarizing interferon pathway state-of-the-knowledge. Here are excerpts supporting your observation of how complicated it is:

Balancing dual roles.
Type 1 interferons (IFN-α/β) may control viral replication and spread through two mechanisms. Antiviral responses include the expression of antiviral genes and the activation of specific immune cells. Immunomodulatory responses include the expression of immunosuppressive molecules, immune cell inhibition, and cell death. The balance of these responses may shift, with enhanced antiviral actions during acute infections and greater immunomodulatory effects during chronic infections....

Why might IFNs elicit direct antiviraleffects while concurrently boosting immunoregulatory responses that prevent robust adaptive immune responses to infections? One possibility is that the immunoregulatory functions of IFN-α/β may have evolved to limit immune-mediated pathology during infections where viral persistence is inevitable. In these settings, the IFN-α/β pathway may sense the level of ongoing viral replication and bolster immune suppression to avoid damaging immunopathology, such as a “cytokine storm” (uncontrolled cytokine production and immune cell activation), meningitis, or immune-mediated tissue destruction. An essential next step will be determining how this balance is influenced by pathogen virulence and the strength of the immune response. In addition, the ability of IFN-α/β to efficiently control early viral replication, and the capacity of different viruses to evade this response, may dictate the importance of these immunoregulatory effects.

How might these findings improve IFN-based treatment strategies? There are several issues to be addressed. Identifying the molecular basis for the antiviral versus immunomodulatory effects of IFN-α/β will be necessary to selectively manipulate these opposing activities. It will also be critical to determine how the balance between antiviral and immunoregulatory effects varies from virus to virus or during a single viral infection over time. The studies of Teijaro et al. and Wilson et al. suggest that patients currently on IFN therapy could be monitored for the induction of antiviral versus immunoregulatory effects, allowing physicians to modify treatment strategies accordingly. It also may be possible to further improve the antiviral therapeutic potential of IFNs and perhaps exploit the immunoregulatory properties of this pathway for nonviral diseases.

 

[Hip]

So the the interferon alpha and beta pathways, as well as being antiviral, have built-in brakes that prevent a full-on immune attack, and speculation is that the brakes are used in cases where viral persistence is inevitable, in order to prevent cytokine storms, meningitis, and tissue destruction.

 

[heapsreal]

Apparently people feel like crap when on interferon treatment too.

 

[Gemini]

So the the interferon alpha and beta pathways, as well as being antiviral, have built-in brakes that prevent a full-on immune attack, and speculation is that the brakes are used in cases where viral persistence is inevitable, in order to prevent cytokine storms, meningitis, and tissue destruction.

Hip, what really excited me if I read the papers correctly is they can already pre-screen patients about to undergo antiviral therapy for their "interferon signature" (gene expression) & predict by results of the pre-screen how likely an immunosupressive state will be after therapy starts.

Also monitoring molecular functioning of the interferon pathway during treatment may in the future allow them to block or unblock signaling as needed for successful virus clearance & avoidance of immunosupression.

Most is basic science research but one of the UCLA grants was in the area of Translational Medicine so it seems they really want to get these new techniques into Clinical practice.

 

[Gemini]

Apparently people feel like crap when on interferon treatment too.

heapsreal, I remember reading many years ago about the severe side effects some C patients were experiencing on interferon therapy.

it was I think the similarity of these side effects to many of the ME/CFS symptoms that sparked researchers interest in interferon status. Komaroff reported in 1992 "Some investigators found increased levels of circulating interferon [in ME/CFS patients] while others have not."

I 'd love to see them apply this new "interferon signature" testing in ME/CFS! Especially to patients about to undergo antiviral treatment.

 

[Hip]

I'd love to see them apply this new "interferon signature" testing in ME/CFS! Especially to patients about to undergo antiviral treatment.

Do you know if the interferon signature of an individual is determined by their SNP mutations? Many people on this forum, myself included, possess a data file containing their personal SNP mutation profile (via testing performed at 23andme).

 

[natasa778]

sorry coming to this thread late so not sure if this has been mentioned, but interferon activates something called IDO pathway, which then degrades tryptophan - diverts it away from serotonin/melatonin arm of its metabolism and towards quinolinic acid arm. Meaning negative effects are potentially two-fold: less serotonin/melatonin and niacin and more excitatory/neurotoxic quinolinic acid ... Negative psych/behaviour effects of interferon treatment are widely believed to be primarily down to this mechanism.

(in this context it might be interesting that antivirals such as acycolvir/valacyclovir can kick interferon into action, or in any affect IDO pathway, which is most likely imo behind initial negative symptoms when starting those... also why niacin sometimes can help, via negative feedback, or serotonin boosting sups)


http://en.wikipedia.org/wiki/File:Tryptophan_metabolism.png

 

[Hip]

Interferon activates something called IDO pathway, which then degrades tryptophan - diverts it away from serotonin / melatonin arm of its metabolism and towards quinolinic acid arm

I believe that is the reason that interferon therapy can cause significant dperession: because it reduces serotonin production. Low serotonin can cause depression or irritability.

 

[Gemini]

Do you know if the interferon signature of an individual is determined by their SNP mutations? Many people on this forum, myself included, possess a data file containing their personal SNP mutation profile (via testing performed at 23andme).

Hip,

Interferon signature genes are cited here. Don't know if they match up to 23 andme SNPs, perhaps the company could tell you if they test for any of the known INF genes?

Interferon signature now used as a biomarker in RA, Lupus, MS, etc. as well as in infectious disease treatment trials.

I'd love to see the patients in the new Ampligen study tested for their interferon signature! Might answer the question why some are responders and others not.

The interferon type I signature towards prediction of non-response to rituximab in rheumatoid arthritis patients.

Department of Rheumatology, VU University medical center, de Boelelaan 1117, Amsterdam, 1081HV, the Netherlands. c.verweij@vumc.nl.

Abstract

B cell depletion therapy is efficacious in rheumatoid arthritis (RA) patients failing on tumor necrosis factor (TNF) blocking agents. However, approximately 40% to 50% of rituximab (RTX) treated RA patients have a poor response. We investigated whether baseline gene expression levels can discriminate between clinical non-responders and responders to RTX.

METHODS:

In 14 consecutive RA patients starting on RTX (test cohort), gene expression profiling on whole peripheral blood RNA was performed by Illumina® HumanHT beadchip microarrays. Supervised cluster analysis was used to identify genes expressed differentially at baseline between responders and non-responders based on both a difference in 28 joints disease activity score (ΔDAS28 < 1.2) and European League against Rheumatism (EULAR) response criteria after six months RTX. Genes of interest were measured by quantitative real-time PCR and tested for their predictive value using receiver operating characteristics (ROC) curves in an independent validation cohort (n = 26).

RESULTS:

Genome-wide microarray analysis revealed a marked variation in the peripheral blood cells between RA patients before the start of RTX treatment. Here, we demonstrated that only a cluster consisting of interferon (IFN) type I network genes, represented by a set of IFN type I response genes (IRGs), that is, LY6E, HERC5, IFI44L, ISG15, MxA, MxB, EPSTI1 and RSAD2, was associated with ΔDAS28 and EULAR response outcome (P = 0.0074 and P = 0.0599, respectively). Based on the eight IRGs an IFN-score was calculated that reached an area under the curve (AUC) of 0.82 to separate non-responders from responders in an independent validation cohort of 26 patients using Receiver Operator Characteristics (ROC) curves analysis according to ΔDAS28 < 1.2 criteria. Advanced classifier analysis yielded a three IRG-set that reached an AUC of 87%. Comparable findings applied to EULAR non-response criteria.

CONCLUSIONS:

This study demonstrates clinical utility for the use of baseline IRG expression levels as a predictive biomarker for non-response to RTX in RA.

PMID:
22540992 April 2012
[PubMed - indexed for MEDLINE]

 

[Hip]

Regarding the interferon type I response genes in the above study, namely the genes: LY6E, HERC5, IFI44L, ISG15, MxA, MxB, EPSTI1 and RSAD2.

Some of these genes contain SNPs which have a page on the SNPedia.com website, as this SNPedia website search shows. However, if you look at these SNP pages, there is very little or no information on them at present.

 

[Gemini]

Meaning negative effects are potentially two-fold: less serotonin/melatonin and niacin and more excitatory/neurotoxic quinolinic acid ... Negative psych/behaviour effects of interferon treatment are widely believed to be primarily down to this mechanism.

Thanks natasa, interesting about serotonin/melatonin/niacin & quinolinic acid.

Years ago I remember articles about the negative effects of Hep C interferon therapy ie., severe depression even some suicides which they attributed not to psychological problems but to the biological effects of interferon.

I thought it interesting back then as some ME/CFS investigators considered endogenous interferon a prime suspect. Wakefield & Lloyd noted "that the symptoms of CFS bear a startling resemblance to those of interferon poisoning."

Fast forward to March 2012 an interesting review article from Brain Research "Interferon Modulates Central Nervous System Function:
http://www.ncbi.nlm.nih.gov/pubmed/?term=22322149

 

[Gemini]

Regarding the interferon type I response genes in the above study, namely the genes: LY6E, HERC5, IFI44L, ISG15, MxA, MxB, EPSTI1 and RSAD2.

Some of these genes contain SNPs which have a page on the SNPedia.com website, as this SNPedia website search shows. However, if you look at these SNP pages, there is very little or no information on them at present.

Hip,

Came across an Interferome data base re: interferon regulated-genes, not sure what information is there though:
http://www.ncbi.nlm.nih.gov/pubmed/?term=23203888

Discovery happening at lightning speed it appears!