New Occult Hep C paper from Pham et al

[TnHepGuy_]

Chronic hepatitis C and persistent occult hepatitis C virus infection are characterized by distinct immune cell cytokine expression profiles.

"Hepatitis C virus (HCV) replicates in immune cells in both chronic hepatitis C (CHC) and occult HCV infection, but the extent of virus replication in this compartment in these opposing infection forms varies greatly. It was unknown whether this could be linked to HCV genotype or to differences in host gene expression shaping the immune response, and whether HCV replication in immune cells is sensitive to endogenous antiviral cytokines. In this study, we uncovered that significantly greater HCV load in peripheral blood mononuclear cells (PBMC), but not in plasma, coincided with HCV genotypes 2 and 3 in CHC, but with genotype 1 in residual occult infection after clinical resolution of hepatitis C. Moreover, PBMC from individuals with occult infection transcribed significantly greater levels of IFN-alpha, IFN-gamma and TNF-alpha, but less interleukin (IL)-10 than those from CHC. In CHC, PBMC with low HCV load expressed significantly more IFN-gamma but less IL-12 than did cells with high virus content. In occult infection, HCV RNA detection in PBMC was associated with much lower IFN-alpha and IL-12 expression. Further, HCV replication in T lymphocytes could be completely eliminated by activation of endogenous IFN-gamma in CHC, but of IFN-alpha in occult infection. In conclusion, CHC and persistent occult HCV infection are characterized by clearly different profiles of antiviral cytokine response in circulating immune cells which are also different from those of healthy individuals. Higher expression of IL-10, combined with lower transcription of IFN-alpha, IFN-gamma and TNF-alpha, is associated with a more robust HCV replication in immune cells."

http://www.ncbi.nlm.nih.gov/pubmed/19215578?ordinalpos=1&itool=Email.EmailReport.Pubmed_ReportSelector.Pubmed_RVDocSum


TnHepGuy

[Hepatitis Researcher]

"    - What are the possibilities of occult SVR's being able to transmit the virus?

Most likely negligible, since not even full blown VLs with fit virus in the 5o Million/ml range are very transmissible in the sexual context.


"- And if the majority of occult infection is made of 'unfit' viral remnants, how might the immune system of an uninfected individual who became exposed (via transfusion, IV drug use, needle stick, etc) respond? Would you expect their immune system to 'trap' and treat it in the same way - creating a low level 'balance' with a chronic infection remaining? Or might a healthy immune system be able to fully 'knock back' the occult infection to the point where negative strand replication no longer takes place? "

Such an infection will probably not take hold to any degree that matters. It has become a "non-pathogenic' virus, a lame and tame dog out of a Wolfe....

Questions like that will also have a very low chance of being investigated, since they are very difficult to examine and have a clinical impact too low to matter in a world filled with more obvious diseases and dilemmas.

[Hepatitis Researcher]

"   once again this paper shows a very clear effect of mitogen and PHA/IL2 stimulation of PBMCs on measured HCV RNA. On the other hand, papers like
http://www.ncbi.nlm.nih.gov/pubmed/18593587
which argue for eradication, have not applied this step in their protocol. Any thoughts on why? Even if the stimulation is non-physiologic it seems to be essential to measuring low levels of replication

Well if you think friendly you may argue, that they only wanted to check for Vl levels that are of any relevance..

If you are critical you could say that the inconvenience or unavailability of the stimulation procedure in their labs or the places where they send the material for testing was the real cause for not using it.
It has to be clarified that the stimulation by itself does not produce false pos results, but holds the capacity to enhance extremely minute amounts to the level of very small amounts, possibly by providing enough of the transcription and translation co-factors that the unfit virus needs to manage a few rounds of replication in an otherwise non-conducive cellular environment...
We must keep in mind that "infection" of dendritic cells and macrophages by viruses is not a surprising phenomenon limited to HCV. After all these cells need to take up all those infectious particles intracellularly, so as to present their epitopes to the lymphocytes that need specific education and stimulation. Somehow they manage not to become breeding grounds of virions themselves, again quite an essential feature considering their role in the defense process.

[DoubleDose]

If there is a more fascinating, important, and yet-to-be fully understood aspect of HCV infection and treatment than the Occult/Persistent viral infection research that is being led by Pham, Castillo, etc. then I would love to hear about it!!

This research could potentially answer many questions about how the immune system works in chronic viral infection, and what different forms of chronic infection might mean to the person who is affected by them.  Our simplistic view of SVR meaning "gone baby gone' will probably be replaced by a newer version of some sort of 'viral stasis' in the body, with a host of consequent symptoms, reactions, and internal system alterations reflecting these ongoing attempts at maintaining viral stasis.  

This is exactly why I think we often see the random Post-TX, Post SVR PCR test that comes back in the 40 IU, 60 IU, 90 IU viral load range.  Possibly not a false positive at all, but just the body figuring out how to permanently keep the residual virus under control, and under the current limits of detection.  Too many of these odd, very low level PCR results occur to just be 'false positives!', at least I believe this is the case.

The occult/persistent research also forms a basis for many of my intra-familial observations over the years, where I believe that I have seen typical "HCV extra-hepatic" symptoms in family members, and former partners, who do NOT test positive for the virus.  Maybe the 'cytokine reaction' to having come in contact with spurious HCV virions in saliva, sexual fluids, etc. over many years of contact.

Maybe there is a 'cellular based' occult viral infection that takes residence in others, in salivary glands, sexual organs, or even systemically in CNS, but just like SVR's is always held to a very minute, sub-detectable, and maybe localized infection....nonetheless, triggering continuing cytokine reactions in the host...thus causing a range of observable, and chronic HCV-like symptoms!!!  This form of infection might never trigger humoral cytoking reactions, and thus the blood based anti-HCV tests would always produce a Negative result!  Although there have been a few research articles alluding to this scenario, there has been little interest overall in pursuing these subjects in the wider HCV research community.

You could project this possibility out into the general population, and see how a sizable portion of the population could be impacted by this 'cellular level infection' thus causing an increase in many of the unexplained health trends that we see today in the populace.  Far more chronic inflammatory, allergic, hypertensive, diabetic, depressive, cases, etc. than ever before in history.  I know, its just the fast food chains causing all of it!!! ( I don't buy that theory at all.)

Thanks to all of you for keeping an important issue front and center. Thank you HR for your scientific and clinical input, and professional demeanor.   Occult and Persistent HCV, and Post SVR viral status are the next generation of HCV challenges that need to be met head on, and fully understood.  The implications might be more severe than currently believed, and of wider impact than we suspect.  Sorry for the divergence from the main issue, in my tag-on speculative commentary, but I think there is a connection, so I will continue to discuss my concerns.

Best wishes to all of you!!!

DoubleDose

[TnHepGuy_]

Thanks for all of your thoughts and comments on this paper. I, too, am fascinated by Pham's work in this area. He is a virtual lone wolf (along w/ Castillo et al) in the area of occult/post-SVR research - and I, for one, certainly hope his funding continues into the future and other researchers begin to pay closer attention.

HR - I know this is purely speculative, but I hope you don't mind if I ask your thoughts here:

- What are the possibilities of occult SVR's being able to transmit the virus?

- And if the majority of occult infection is made of 'unfit' viral remnants, how might the immune system of an uninfected individual who became exposed (via transfusion, IV drug use, needle stick, etc) respond? Would you expect their immune system to 'trap' and treat it in the same way - creating a low level 'balance' with a chronic infection remaining? Or might a healthy immune system be able to fully 'knock back' the occult infection to the point where negative strand replication no longer takes place?

And on a personal note, as a post-SVR (4 years and counting), I was wondering what immune enhancement supplements you might think be in order for someone who: a.) may be experiencing negative effects of post-peginterferon exposure, and b.) could possibly be occult-positive. Thank you.


TnHepGuy

[willing]

thanks for posting the article and for the interesting  discussion. I'm a big fan of the work being done by Pham and others at the Michalak lab. The overall conclusion from their data, borne out by many others, is that  SVR is simply a different and stable equilibrium point in the struggle between virus and host. While much of the rest of the research community seems to have decided that this is not an interesting area of research, Pham has been systematically exploring the parameters of this new equilibrium.
The main point of the article was comparison of expression levels between chronic and residual infection, but the comparison with healthy subjects is pretty striking. Cytokine activity in PMBCs reminds me a bit of those stories of isolated Japanese troops fighting long after the end of WWII - no one's told them the war's over. Among the 6  cytokines,  3 IFN-induced genes and 4 CD proteins whose mRNA they quantified, statistically significant differences between healthy and chronic-HCV subjects showed up in four: IFN-a, IP-10, OAS, and CD19. So what happens after chronic infection is resolved (either spontaneously or through SVR)? Of the four, only  OAS returns close enough to normal levels that the differences are no longer significant.  The health effects, if any,  of the continuing elevated cytokine levels seem likely to remain unclear for a long time to come and none of this diminishes the good news in
http://www.ncbi.nlm.nih.gov/pubmed/19072828
but it's interesting background, and what's special about OAS?

The other major news here, poorly summarized in that unhappy sentence in their abstract, seems to be that genotype  plays a significant role in determining viral replication in immune cells and post-resolution infection. While for g2/g3s the ratio of plasma to pbmc vl looks similar pre/post SVR, with the major difference being the reduction in volume of vl from millions of copies/ml to mere tens, for g1s that ratio is reversed with higher pbmc infection, relative to plasma, post svr. Maybe  g1 virions  reproduce relatively poorly in pbmcs (relative to hepatocytes), but those that do manage the feat are more tenacious post tx?


HR: once again this paper shows a very clear effect of mitogen and PHA/IL2 stimulation of PBMCs on measured HCV RNA. On the other hand, papers like
http://www.ncbi.nlm.nih.gov/pubmed/18593587
which argue for eradication, have not applied this step in their protocol. Any thoughts on why? Even if the stimulation is non-physiologic it seems to be essential to measuring low levels of replication.

[alagirl]

this is further evidence that in some SVR this ongoing innate immune stimulation will have the consequence of increased inflammation, over the level that this person would have had, as a simple age related phenomenon, if never HCV infected. There is not much that can be done about this. It most likely serves to stabilize SVR.
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Fabulous.

Good to see you btw