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HTLV-1's replication: Perhaps it can explain XMRV's low degree of mutations

omerbasket

Senior Member
Messages
510
Today I read a post by "ukxmrv", and that's what he said there:
Dr Mikovits said at the IiME conference in London that HTLV is the virus to think about rather then HIV. With HTLV she said that the virus could be sequenced from the same patient 40 years later and it would be the same.

Also remember Dr Magiorkinis in the Lancet

(start)
Once a virus is endogenised, it is forced to follow the evolutionary rate of the host. Since XMRV is integrated in cell-lines the virus evolution is restricted to the host's pace of evolution, and viral descendants have none or minimum sequence diversity. Thus, if a contaminated product, previously cultured in cell-lines, is administered to people then the infections would provide the evolutionary patterns reported by Hue and colleagues.4 If the immunological data reported by Lombardi and colleagues5 are correct, then we need to trace the common source for these infections to prevent possible public health concerns. Products from cell-lines should be the first candidates.
So then I searched for papers about HTLV-1's replication, to see if it can give us hints about why XMRV has a low mutation rate, if it has a low mutation rate (which I'm not sure of - because I don't know if the Lo/Alter sequences shouldn't be called "XMRV" - in fact, I don't understand why they don't call them by that name - and they represent a significant mutation rate from VP62).

Anyway, I think that I found some interesting stuff (Warning: I'm not a scientist, and it's very possible that I'm wrong in some of the things that I say. If you know that I'm wrong, or think that I'm wrong - please say so and say why):
1) It seems that HTLV-1's main route of replication is not by reverse transcriptase of the virion (virion is the infectious virus particle when it's OUTSIDE of the host's cell) - like most of the retroviruses (inlcudin HIV-1) - but through another mechanism: It replicates with with the cell - when the cell replicates, the virus replicates. Here are some parts of studies where they talk about that:
Although HTLV-1 can replicate via the reverse transcription of virion RNA to a double-stranded DNA provirus (the conventional manner for retroviruses), its predominant mode of replication is via the clonal expansion (mitosis) of the infected cell.
http://jnci.oxfordjournals.org/content/93/5/367.full

These observations indicate that while the mutation rate of HTLV-1 is significantly lower than HIV-1, this lower rate alone would not explain the low diversity in HTLV-1 isolates, supporting the hypothesis that HTLV-1 replicates primarily as a provirus during cellular DNA replication rather than as a virus via reverse transcription.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC112382/
We conclude that, as HTLV-1, STLV-1
mainly replicates by the clonal expansion of infected cells

So, perhaps XMRV is replicating like HTLV-1 - mostly through cell division and less by reverse transcriptase of the virion. And that would cause it to have less mutations:
DNA replication by cellular DNA polymerases is
known to be a high-fidelity process and typically is a minor
contributor to retrovirus variation
http://jnci.oxfordjournals.org/content/93/5/336.full.pdf
2) HTLV-1 has an oncogene - it's called "tax". XMRV doesn't have an oncogene (its only genes are gag, envelope and polymerase). Now look what they say about the "tax" gene in HTLV-1:
Although HTLV-1 can replicate via the reverse transcription of virion RNA to a double-stranded DNA provirus (the conventional manner for retroviruses), its predominant mode of replication is via the clonal expansion (mitosis) of the infected cell. This expansion is achieved by the viral oncoprotein Tax, which keeps the infected CD4 T lymphocyte cycling. Because Tax also interferes with cellular DNA repair pathways, we investigated whether somatic mutations of the provirus that occur during the division of infected cells could account for HTLV-1 genetic variability
http://jnci.oxfordjournals.org/content/93/5/367.full
Although the fidelity of cellular DNA replication is high, the
expression of the HTLV-1 Tax protein has been shown to influence
cellular DNA repair pathways, the cellular mutation frequency,
and the transition from G1 to S phase (11,12). These
studies together create a picture that indicates that HTLV-1 replicates
primarily as a provirus through continual host cell proliferation
and that Tax induces genetic instability of HTLV-1
and the infected cell.
http://jnci.oxfordjournals.org/content/93/5/336.full.pdf
So, when HTLV-1 is causing cancer - you should expect - if I understand it correctly - to find a greater variability than when it doesn't, and that's because when you have cancer, you cells are dividing more often - which would give HTLV-1 more opportunity to change his genome. Also, theye say that the "tax" gene interferes with cellular DNA repair pathways, so perhaps that's also helping it mutate, I think.

Now, a cancer caused by XMRV might be a different thing, but when you are talking about XMRV in patients without cancer - and if XMRV replicates in a similar way to HTLV-1, meaning, mostly by cell-division - I think that you should expect that XMRV would even have less mutations, because if there is no cancer, than the cells are dividing much slower, giving XMRV much less opportunities to change its genome. And even if you do have cancer - if I understand correclty, retroviruses without oncogenes (as XMRV is) can cause cancer, but in a different way (I think it depends on where they integrate - whether they integrate into an oncogene or something like that), and XMRV won't have the "tax" gene that would interfere with cellular DNA repair pathways - so even if you have cancer, you might expect lower variation of XMRV, in comparison to HTLV-1.

3) Even when HTLV-1 virions are replicating, using reverse transcriptase, it seems that their mutation rate is significantly lower than the mutation rate of HIV-1:
The in vivo mutation rate for HTLV-1 was determined to be 7 10?6 mutations per target base pair per replication cycle. The majority of the mutations identified were base substitution mutations, namely, G-to-A and C-to-T transitions, frameshift mutations, and deletion mutations. Mutation of the methionine residue in the conserved YMDD motif of the HTLV-1 reverse transcriptase to either alanine or valine (i.e., M188A or M188V) led to a factor of two increase in the rate of mutation, indicating the role of this motif in enzyme accuracy. The HTLV-1 in vivo mutation rate is comparable to that of bovine leukemia virus (BLV), another member of the HTLV/BLV genus of retroviruses, and is about fourfold lower than that of HIV-1.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC112382/
4) You must remember that while HTLV-1 is a complex retrovirus, XMRV is a simple retrovirus. As far as I understand it, simple retroviruses, because of the small number of genes, are mutating less than complex retroviruses, which have more genes (while XMRV has 3 genes - gag, polymerase and envelope - HTLV-1 has 5 genes: gag, polymerase, envelope, tax and rex).

Now, it seems that XMRV is a retrovirus that is replicating slowly and that usually has little variation. One way of explaining this would be to say: "It's just contamination". But another way would be: "Hey, we already know of a human retrovirus that replicates slowly and that has little variation. And we can also see that if XMRV replicates mostly by cell-division, than it would be expected that it would replicate even less than HTLV-1 and would have even less variation than HTLV-1".

Now, there is another thing, and that's regarding the PMRVs found by Lo and Alter (and their colleagues - I must mention them as I think it's unfair to them that we never mention their names... so: Natalia Pripuzova, Guo-Chiuan Hung, Bingjie Li, Richard Wang and Anthony Komaroff): These sequences are "just" 84%-96% (mostly about 95%) identical to the VP62-strains. Since HIV-1 and HCV (and probably many other viruses that I did not check) has strains that are only 85% and 79% identical to one another - and still all of these are named "HIV-1" and "HCV", I currently don't understand why some of the scientists say that the PMRVs and XMRV are different viruses. So, let's assume that they are the same virus - which in my unscientifically-educate opinion is the more reasonable thing to think - how would we explain why those strains have more variability? I mean, we just explained why you might not expect XMRV to have a large variability. I think I might have an explanation for that:
It has been shown previously (4) that
HTLV-1 isolates from Japan have about 97%99% homology
and that isolates from Japan, the Caribbean, and Africa can
also share as much as 96%99% homology. HTLV-1 isolates
endemic in different races have been suggested to be of utility
in studying the movement of ancient human populations or in
anthropologic studies (5). However, HTLV-1 isolates from
Melanesia would not be as useful as isolates from Japan, the
Caribbean, and Africa in anthropologic studies because there is
not as much sequence homology to the original Japanese isolate(6).
http://jnci.oxfordjournals.org/content/93/5/336.full.pdf

Here, we report the complete nucleotide sequence of an HTLV-I isolate (designated HTLV-I-MEL5)
from the Solomon Islands. The overall nucleotide divergence of HTLV-IMEIZ from the prototype
HTLV-I-ATK was approximately 8.5%.
http://jvi.asm.org/cgi/reprint/67/2/1015.pdf
So there, they found a strain of HTLV-1 that was "only" 91.5% identical to the reference strain (and actually, I think, that was about the percentage of difference from other strains too). All of the other strains (and I did not find many complete genome strains, unfortunately) are highly identical to one another, as was said in one of the quotes above. It should be said, however, that this strain was found in Oceania while the reference strain was from Japan - and in our case the PMRVs were found in the USA, although in another state (but anyway Dr. Mikovits is finding the P strain also in her samples, which I guess are mostly from Nevada, although I can't be sure of that - but it's probable that she finds the P variant at least in some samples from Nevada). So I don't know how to explain that, but even if nobody knows how to explain that, there could be an explanation - and actually I guess that scientists can give numerous explanations for that, at least if they would think about it deeply.

Anyway, I think that what we can see is the following:
1) There is already an example of a human retrovirus that replicates slowly and have little variability in the vast majoirty of its strains.
2) It's reasonable to expect that XMRV would have even less variability, and I explained why.
3) Despite usually having a low degree if variability, HTLV-1 does have a strain that is subtantially mutated - although that's from another part of the world, and the PMRVs are from a place pretty close to where the XMRVs where found (and anyway the WPI found PMRVs in their samples - probably from Nevada also - and XMRVs in the Lo/Alter samples).
4) I didn't talk about it in the above text, but I think that one bad, very bad thing that we might have to deal with if the thoery that XMRV replicates much like HTLV-1 is correct (and it's important to say that right now it's just a theory, and we, or at least I, cannot know if that theory is correct or not) is that it would probably be hard to fight it with antiretrovirals - because, at least as far as I understand it, when the virus is replicating by the cell-division route, it doesn't do all the reverse transcription and things that it does when it replicates outside of the cells, and therefore - and correct me if I'm wrong - the antiretrovirals that works against HIV won't be of a major help, because I think that they are acting only against a virus that replicates in a way different from replication by cell-division. I would like to say, however, that my hunch is that in the very-sick patients there is probably more viral replication by the reverse transcriptase route, and therefore perhaps anti-retrovirals can help them more, although just to some degree (because than you arrive at the cell-division replication, and as I said, I think that antiretrovirals does not act against that). By the way, I think that somewhere here or in the other forum it was posted before about scientists who are trying to eliminate retroviruses with a method that is based on chemotherapy - and it seems to me that this is the kind of things that can help those who are sick due to integrated retroviruses (in order to eliminate the cells that have retroviruses integrated into them). If they would be able to attack only, or at least mostly, the cells that have a provirus of XMRV integrated into them, I think that might be fantastic.

I would very much like to hear your thoughts about that - and if I was mistaken somewhere, please correct me (but also explain why you think I was wrong).
 

omerbasket

Senior Member
Messages
510
By the way, I don't know how to change the title from "explains" to "explain" - can a moderator change that for me? Thanks :)
 

Jemal

Senior Member
Messages
1,031
Omer, I enjoyed reading it and I think you did a good job of making yourself understandable, even when talking about a complex topic. I can only say I think you have a point. I say "I think", because you are going pretty deep into the science here and to evaluate if you really have a point, we would need someone who understands the science better than you and I do.

As for point 4: I think we heard quite soon after XMRV was linked to CFS by the WPI, that the virus probably replicates slowly (and maybe differently, as you said). As antiretrovirals hit a virus when it replicates, that didn't bode too well...
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
Hi omerbasket, wow. I am too brain dead at the moment to follow up on most of this, so I just want to write a few comments.

X/P MLVs don't care what we call them. They are similar, and recombine. A large part of the diversity is probably recombination. The thing is an X can't infect mice, a P can, but I have not looked into the details of the receptor interaction. I guess its a small mutation, one way or the the other. If this is right, its just a tiny genetic variation, with a large functional impact. That is why they say it is different, but it is best thought of as the same virus, just a slight variant in my opinion.

The issue with whether or not ARVs are ideal for fighting XMRV has been discussed before, somewhere on PR some time ago. The idea is to reduce blood viral load, and so the immune response especially cytokines. At least that is how I see it. It will never be a cure. By reducing blood load, it will reduce spread, and reduce immune damage from us fighting it - and that damage may be a big part of ME/CFS. In other words, it might suppress ME/CFS symptoms, but leave the infection relatively untouched.

This is a big problem, which a whole lot of very smart scientists will have to work on for a whole lot of years, and a whole lot of dollars, before we see a cure. The best we can hope for is symptom reversal - my guess is most of us can get back to severnty or ninety percent capacity, which is good enough for me to be happy about - presuming of course that XMRV is either causal or co-causal.

I am glad you looked into HTLV, we have needed this for some time. Maybe others can add to your analysis.

Bye
Alex
 

omerbasket

Senior Member
Messages
510
I say "I think", because you are going pretty deep into the science here and to evaluate if you really have a point, we would need someone who understands the science better than you and I do.
I totally agree with that. Although the laymen discussions are also good, even if not good enough, and we can also contribute with our ideas and with what we think about the ideas of others.

But sure, we do need people who understand the science enough in order to help us on such matters.
 

Marco

Grrrrrrr!
Messages
2,386
Location
Near Cognac, France
Nice one Omer and very clearly explained.

The lack of sequence variation has been a sticking point and clonal expansion could explain a lot; including the apparently mixed reaction to ARVs with the few who have tried them and the finding that the human immune response at least partially inhibits XMRV does not preclude an ongoing chronic infection.

I never could buy the argument that XMRV and Lo/Alters' Poly sequences are 'not the same' while at the same time saying that lack of variation in XMRV meant contamination. At what stage is too little variation to be 'real' become too much to be the same?

As for host range, some of the main critics even identified the variants many years ago and considered them 'closely related'.

The four classes of endogenous murine leukemia virus: structural relationships and potential for recombination.

J P Stoye and J M Coffin



We conclude that all the proviruses can be assigned into one of four different classes: the previously characterized ecotropic, xenotropic, and polytropic viruses, as well as a new class we have termed modified polytropic viruses. The xenotropic, polytropic, and modified polytropic classes are closely related to one another, but as a group they differ considerably from the ecotropic class.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC255766/?tool=pmcentrez

I've been doing a little reading up on HTLV's also and there's a lot of known data that can help explain the divergent findings to date. What also struck me is that the same names keep cropping up (from both sides of the argument). They all know (or know of) each other and have access to the same research going back many years if not decades.

Good old fashioned professional rivalry and/or entrenched opinions could explain a lot.
 

Bob

Senior Member
Messages
16,455
Location
England (south coast)
Great research Omerbasket... Thanks very much for that... It demonstrates that the subject of virology is so much more complex, diverse and unpredictable than even many of the virologists are acknowledging when making their predictions and conclusions.
 

anciendaze

Senior Member
Messages
1,841
Good work, Omerbasket.

I would like to point out that HTLV-1 is a delta retrovirus. There are leukemia viruses in the same genus, and frequent recombination in the wild can make nonsense of taxonomy imposed by human scientists. I've been talking about bovine leukemia virus as a model for months, because it has far more latent provirus than active viral infections in blood. The reported ratio is between 1 in 5,000 and 1 in 50,000 actively infected cells. BLV interacts with the host life cycle in much the way MLV does, but the time scale is considerably longer. It is important that it slow replication so it does not kill the host before it passes the infection to a new generation.

For human hosts, the time between vertical transmission and reproduction is longer than just about any other mammal; only elephants come close. We should expect to see exaggerated latency as a result, in a well-adapted leukemia virus. Only the relatively recent origin of the XMRV strain caused it to be found. I'm betting on the existence of other retroviruses with the same 'strategy'.
 

Jemal

Senior Member
Messages
1,031
I just saw another post on this forum that I thought was very interesting. In a study in 2006 they found a large part of people infected with HTLV-I had fibromyalgia.

RESULTS: One hundred individuals with HTLV-I infection and 62 non-infected blood donors were studied. Thirty-eight (38%) HTLV-I infected individuals and 3 (4.8%) individuals from the control group presented the diagnosis of FM (OR 12.05, 95% CI 3.53-41.17). Other rheumatic diseases were also more prevalent in the infected group (37% vs 12.9%; OR 3.80, 95% CI 1.63-8.86). In multivariate analysis adjusted by the covariables, the association between HTLV-I and FM was statistically significant (OR 9.14, 95% CI 2.42-34.52).

See:
http://forums.phoenixrising.me/showthread.php?12325-HTLV-1-amp-2-Antibody-Test-Online

Until now I heard that HTLV-I might cause disease in only 5 - 8% of the infected... but it might be much higher?

I find this interesting, because I was a fibromyalgia patient, before I got ME/CFS (and fibromyalgia also being associated with ME/CFS and XMRV).
 

Overstressed

Senior Member
Messages
406
Location
Belgium
I find this interesting, because I was a fibromyalgia patient, before I got ME/CFS (and fibromyalgia also being associated with ME/CFS and XMRV).

Have you been tested on HTLV, Jemal ? I have been tested a few times, lastly with a test that's used in research. According to the HTLV-researcher, HTLV serological tests can give FALSE negatives, due to low virus numbers and accordingly, low antibodies. Sounds familiar ? They carried out a more sensitive test on me and it was negative.

Just a thought...
 

Jemal

Senior Member
Messages
1,031
Have you been tested on HTLV, Jemal ? I have been tested a few times, lastly with a test that's used in research. According to the HTLV-researcher, HTLV serological tests can give FALSE negatives, due to low virus numbers and accordingly, low antibodies. Sounds familiar ? They carried out a more sensitive test on me and it was negative.

Just a thought...

I have been tested for HIV multiple times, but I never noticed HTLV on the forms the doctor filled out. So yes, this post also made me think about getting tested for HTLV.

At least it looks like I don't have HIV... Oh, I was also tested for mad cow disease at one time I think.
 

ukxmrv

Senior Member
Messages
4,413
Location
London
That's interesting OS, I was tested for HTLV-1 at a UK NHS hospital and it was negative. I'll have to check up on more sensitive tests.

In "Osler's Web" it was reported that a lot of Dr Cheney's patients tested positive for HTLV in the early days. I wonder if the test were reacting to something else that the patients had, it was only this one group or the modern tests don't pick up a strain CFS patients have?
 

Overstressed

Senior Member
Messages
406
Location
Belgium
Hi UK,

I remember something I recently read or heard from the symposium about cross-reactivity between conserved regions of XMRV and HTLV. Apparantly, the test cross-reacts to that...

I would contact a HTLV-researcher in order to get this test used within research. Unfortunately, I forgot the name of the test.
 

heapsreal

iherb 10% discount code OPA989,
Messages
10,089
Location
australia (brisbane)
That's interesting OS, I was tested for HTLV-1 at a UK NHS hospital and it was negative. I'll have to check up on more sensitive tests.

In "Osler's Web" it was reported that a lot of Dr Cheney's patients tested positive for HTLV in the early days. I wonder if the test were reacting to something else that the patients had, it was only this one group or the modern tests don't pick up a strain CFS patients have?

probably just contamination, they just need to exercise more, lol. lots of sarcasm present in my post. I just hope they keep looking for some infectious cause as our immune profiles show something is going on with elevated l-rnase and poor nk function, unless we have an immune defiency which is why alot of us test positive to all these viruses reactiviating.

cheers!!!
 

Bob

Senior Member
Messages
16,455
Location
England (south coast)
These papers are relevent to the discussion regarding low mutation rates...
I'm just posting them so we have easy reference to them...

Low Degree of Human T-Cell Leukemia/Lymphoma Virus Type I Genetic Drift In Vivo as a Means of Monitoring Viral Transmission and Movement of Ancient Human Populations
ANTOINE GESSAIN, ROBERT C. GALLO, AND GENOVEFFA FRANCHINI
21 October 1991
http://jvi.asm.org/cgi/reprint/66/4/2288

Complete Nucleotide Sequence of a Highly Divergent Human T-Cell Leukemia (Lymphotropic) Virus Type I (HTLV-I) Variant from Melanesia: Genetic and Phylogenetic Relationship to HTLV-I Strains from Other Geographical Regions
ANTOINE GESSAIN, ENZO BOERI, RICHARD YANAGIHARA, ROBERT C. GALLO, AND GENOVEFFA FRANCHINI
12 November 1992
http://jvi.asm.org/cgi/reprint/67/2/1015.pdf

The Low Evolutionary Rate of Human T-Cell Lymphotropic Virus Type-1 Confirmed by Analysis of Vertical Transmission Chains
S. Van Dooren, O. G. Pybus, M. Salemi, H.-F. Liu, P. Goubau, C. Remondegui, A. Talarmin, E. Gotuzzo, L. C. J. Alcantara, B. Galvo-Castro, and A.-M. Vandamme
January 22, 2004
Molecular Biology and Evolution
http://mbe.oxfordjournals.org/content/21/3/603.full
 
Messages
51
Location
Newark, NJ
Omerbasket - I love your original post and find myself reading it again & again.
Overstressed - the typical test for HTLV is the antibody test, the "more sensitive" test is for HTLV is the PCR test.