Infection, viral dissemination and antibody responses of Rhesus macaques

[urbantravels]

Infection, viral dissemination and antibody responses of Rhesus macaques exposed to the human gammaretrovirus XMRV

J. Virol. doi:10.1128/JVI.02411-10
Copyright (c) 2011, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

http://jvi.asm.org/cgi/content/abstract/JVI.02411-10v1

Nattawat Onlamoon, Jaydip Das Gupta, Prachi Sharma, Kenneth Rogers, Suganthi Suppiah, Jeanne Rhea, Ross J. Molinaro, Christina Gaughan, Beihua Dong, Eric A. Klein, Xiaoxing Qiu, Sushil Devare, Gerald Schochetman, John Hackett Jr., Robert H Silverman, and Franois Villinger*

Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta GA; Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH; Division of Pathology, Yerkes National Primate Research Center, Emory University, Atlanta, GA; Glickman Urological and Kidney Institute and LRI, Cleveland Clinic Foundation, Cleveland, OH; Abbott Diagnostics, Emerging Pathogens and Virus Discovery, Abbott Park, IL

Abstract

XMRV was identified in association with human prostate cancer and chronic fatigue syndrome. To examine the infection potential, kinetics, and tissue distribution of XMRV in an animal model, we inoculated 5 macaques with XMRV intravenously. XMRV established a persistent chronic disseminated infection, with low transient viremia and provirus in blood lymphocytes during acute infection. Although undetectable in blood after about a month, XMRV viremia was reactivated at 9 month confirming the chronicity of the infection. Furthermore, XMRV gag was detected in tissues throughout, with wide dissemination throughout the entire period of monitoring. Surprisingly, XMRV infection showed organ specific cell tropism: CD4 T cells in lymphoid organs including the gastrointestinal lamina propria, alveolar macrophages in lung, and epithelial/interstitial cells in other organs, including the reproductive tract. Of note, in spite of the intravenous inoculation, extensive XMRV replication was noted in prostate during acute but not chronic infection, even though infected cells were still detectable by FISH in prostate at 5 and 9 months post infection. Marked lymphocyte activation occurred immediately post infection, but antigen specific cellular responses were undetectable. Antibody responses were elicited and boosted upon reexposure, but titers decreased rapidly suggesting low antigen stimulation over time. Our findings establish a nonhuman primate model to study XMRV replication/dissemination, transmission, pathogenesis, immune responses and potential future therapies.

 

[alex3619]

Hi urbantravels, this is interesting. I can't get the full paper, that is a pay only site. One thing came to my attention though. The antibody responses are only really detectable during episodes of acute viral infection. Most of the time antibodies titres are low. This could easily explain why serology testing for XMRV is such a problem. There is usually not anything there to find. It also implies that testing should occur after recent relapse, in which XMRV is more likely to have replicated in numbers.

Bye
Alex

 

[SOC]

How does this report about antibody responses only being detectable during acute episodes affect the information we have from WPI? For example, if XMRV antibodies are not (or minimally) detectable except during acute episodes, could many more healthy people be infected and not showing up in serology tests? This would be bad for us, because we might find that XMRV is nearly universal and not specific to us.

Culture tests are not detecting antibodies, correct? So culture tests should still be able to distinguish...? So does this study provide strong evidence that serological antibody tests are next to useless for detecting XMRV infections?

Sorry, my medical knowledge is not great.

 

[Cort]

The WPI was able to find XMRV using PCR, culture and antibodies in the original paper - which suggests that either they were looking at really ill people - whose virus was reactivated or they can find it in people with CFS who've been infected. Based on all the trouble finding it I would pick answer A at this point.

I don't know how these tests compare to humans but the antibody were an important part of the WPI paper and, of course, they've been giving them for quite awhile now. I would guess they must be useful - but perhaps not as reliable an indicator as one might like. Alot of groups are working on antibody tests; at some point this should be a strength in the field.

They culture the virus and then pick it up using PCR I think.

Its interesting they found it in the gut given all the attention the gut is getting. I think we pretty much know it doesn't do much in T-cells (?). Macrophages are part of PBMC's so we can guess replication is really low in those as well which leaves the epithelial cells. It was found replicating in the prostate as well - which we knew. We want to find a tissue reservoir other than the prostate in CFS; the brain, pituitary, hypothalamus, the spleen ? - and some cell that it's going bonkers in - it doesn't look like that was so in the primates - since they focused on replication in the prostate.

All in all - my take is that a) yes it spread rapidly and apparently disseminated itself throughout the body - so there is the potential to cause alot of damage. The missing piece is evidence that its really active anywhere other than the prostate. From the abstract it doesn't look like they found that. Retroviruses do not necessarily, on the other hand, need to be active to cause damage; HTLV is apparently not very active and it can cause alot of damage in the right person.

 

[cigana]

Its interesting they found it in the gut given all the attention the gut is getting. I think we pretty much know it doesn't do much in T-cells (?)
.

Hi Cort,

Doesn't the abstract mention CD4+ T-cells? Or do you mean though it's there, it doesn't do much?

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What I also found interesting was the presence in "alveolar macrophages in lung" - seems to link in nicely with the German study finding XMRV in the respiratory tract of immuno-compromised patients.

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Hi Alex,

PM me if you want the full text.

Cheers,

Mark

 

[Jemal]

This is a nice writeup from Amy Dockser Marcus on this study. She's still following the story, very nice.
http://blogs.wsj.com/health/2011/02...us-can-cause-persistent-infection-in-monkeys/

This is a tantalizing finding because it raises the prospect that someone could be infected with XMRV but show no clinical symptoms of disease until years, possibly decades, later.

This is pretty interesting. It seems more and more likely that it could takes decades, before you get ill. This means that if 8% of the population is infected, they could potentially all get health problems sooner or later. That might keep the pressure on.

 

[Mark]

OK: so now it's surely indisputable that XMRV can infect monkeys (at least), that it establishes a persistent but hard-to-detect infection in them, and that in this animal at least, it replicates in the prostate.

Several Prostate Cancer studies found XMRV in human prostate cancer. Is it now likely this is all just a coincidence, and that XMRV does not, in fact, infect the human population to significant levels, and that the positive PC studies were simply wrong, and were detecting some sort of contamination...but that despite that it turns out that, by coincidence, XMRV does replicate in the prostate of monkeys, but isn't in humans at all?

I don't think that's likely. Since it turns out that XMRV really does head off to the prostate in monkeys, it seems to me very likely that the prostate cancer studies that all found it at roughly 25% vs 5% in controls, were correct in their findings.

That last leap might be rather less than 100% solid...but the next one is not:

If the positive Prostate Cancer/XMRV studies are right, then the negative papers on XMRV/CFS are wrong.

The PC studies all found XMRV at around 5% in the control groups. The negative studies all found no XMRV, anywhere. If XMRV really is present in around 5% of the population, those negative studies just don't have valid tests that detect XMRV in humans - or they would have at least found it at low levels. It's that simple. Geographic factors can't explain it, across multiple studies in multiple countries.

There is nothing new in this publication to most of us here, I think - we had all this information about 6 months ago (unless I'm mistaken?). But until it was published today, these facts didn't exist at all to the scientific world - you couldn't have cited this one on Bad Science for example, because it hadn't been published yet - they would have snorted and mocked about how unreliable conference presentations are (and probably taken the opportunity to call you an idiot). So although this publication tells us XMRV-watchers pretty much nothing new, it might be big news to the wider scientific community - facts that aren't yet published don't exist, as far as some people are concerned...

 

[Snow Leopard]

Yes, the prostate cancer XMRV research is in the same boat as the CFS research. Both will live or die together. As a few people keep insisting, if the prostate cancer link grows stronger, then we can leverage this due to the whole rich-male at risk of prostate cancer scenarion.

 

[taniaaust1]

. Antibody responses were elicited and boosted upon reexposure, but titers decreased rapidly suggesting low antigen stimulation over time.

In my case I have a mystery going on.... that is why couldnt I kiss a past boyfriend without making him sick the next day (for several days). Is it possible that his sore throat and feeling unwell may of been due to XMRV exposure from me? Would something which is eliciting antibody responses in someone time and time again as this study shows happens, cause a sore throat and some general unwellness each time on each exposure for a short time?

(after the third Id made him ill, we thought it just too coincidental for it to be coincidence and he'd had enough of that going on.. so we ended up having to have a no kissing relationship). Something in my saliva was making him sick even on reexposure. Interestingly.. the other couple of past boyfriends I had, kissing them didnt make them sick ... but my sister used my glass and now appears to have CFS/ME to.

 

[omerbasket]

I think it's possible that she has ME/CFS because of other reasons. Like, for example, vertical transmission. Did she get ME/CFS right after using your glass?