Human APOBEC3 proteins can inhibit XMRV

Jemal

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Is this new? Publication date is 3 dec.

Xenotropic murine leukemia virus-related virus (XMRV) is a novel retrovirus, related to murine leukemia virus (MLV), that has been implicated in human disease. If XMRV is indeed able to replicate in humans, then one might predict that XMRV would have developed resistance to human innate antiviral resistance factors such as APOBEC3G (hA3G). In fact, we observed that XMRV and MLV are both highly sensitive to inhibition by hA3G and equally resistant to inhibition by murine APOBEC3. While several human prostate cancer cell lines were found to lack hA3G, stable expression of physiological levels of hA3G rendered these cells refractory to XMRV replication. Few human tissues fail to express hA3G, and we therefore hypothesize that XMRV replicates in one or more hA3G-negative reservoir tissues and/or that human XMRV infections are likely to be rare and potentially of zoonotic origin.
http://www.ncbi.nlm.nih.gov/pubmed/21131013

The last sentence doesn't really sound hopeful...

It's going to appear in Virology.
 

alex3619

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Hi Jemal, the last sentence of the article you quoted says, in a nutshell, that either we rarely have XMRV or that we only have it in selected tissues. Given we know it has tissue specificity from the animal studies, this is not a surprise. Also APOBEC3 is likely to be one of the reasons this virus is so hard to find in blood. This does not mean we don't have XMRV, it means if we have it we aren't entirely defenseless. It might however explain why XMRV transmission rates are so low - most people probably fight it off, most of the time. However, I worry that the prevalence is so high that even if somebody fights it off 99% of the time, the number of times they have to do this is growing so huge that in time everyone who has no genetic immunity will catch it.

Of course all this is tentative pending better research. Bye, Alex
 

natasa778

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They forgot to mention that MulVs have a way of inactivating human APOBEC3 !!

(It makes sense that this would happen only after a certain period and not be observable within a short study time)
 

Cort

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I don't think this is unexpected. The APOBEC 3G enzymes beats the heck out of XMRV. If its going to be doing damage it would seem that it would have to be doing it in cell without that enzyme. He says most cells have that enzyme...the question is which cells do not and where are they?
 

alex3619

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I don't think this is unexpected. The APOBEC 3G enzymes beats the heck out of XMRV. If its going to be doing damage it would seem that it would have to be doing it in cell without that enzyme. He says most cells have that enzyme...the question is which cells do not and where are they?
Hi Cort, this is a very important question you raise and will tell us which types of cancer we might get, which tissues to biopsy for testing, and where the virus is hiding (so we can target it properly). Bye, Alex
 
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APOBEC3 and an XMRV drug

It seems that an anti-XMRV drug based on APOBEC3 (either a mimic or APOBEC3 stimulant) would be very effective against XMRV and low toxicity (since the cells already use it naturally). I wonder if any of the XMRV drug researchers are looking into this.
 

garcia

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It seems that an anti-XMRV drug based on APOBEC3 (either a mimic or APOBEC3 stimulant) would be very effective against XMRV and low toxicity (since the cells already use it naturally). I wonder if any of the XMRV drug researchers are looking into this.
I believe interferon boosts APOBEC3, so interferon-boosters (such as cycloferon) would be one potential avenue to explore.
 

Jemal

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Ha! I was already wondering where I could sign up for pills that stimulate APOBEC3 :D

The question is though: is boosting effective for areas that lack this defensive protein?
 

FunkOdyssey

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This is interesting: from some very preliminary research, interferon-alpha is the primary interferon inducer of APOBEC3, not interferon-gamma. Yet immunovir helps many patients, and it does not seem to boost IFN-alpha (only IFN-gamma). Maybe it helps control the secondary infections or hits XMRV from another angle.

Cycloferon DOES increase interferon-alpha production, so that is sounding increasingly promising.
 

FunkOdyssey

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IL-2 seems to be important for APOBEC3G production as well. See:

Quantitative profiling of the full APOBEC3 mRNA repertoire in lymphocytes and tissues: implications for HIV-1 restriction

Maybe that's how immunovir helps.
J Interferon Cytokine Res. 2010 Apr;30(4):223-8.
Isoprinosine affects serum cytokine levels in healthy adults.

Petrova M, Jelev D, Ivanova A, Krastev Z.

Medical Institute Ministry of Interior, Sofia, Bulgaria. mpetrova@gmail.com
Abstract

Isoprinosine is a synthetic purine derivative with immunomodulatory and antiviral properties, which result from an apparent in vivo enhancement of host immune responses. To evaluate the serum levels of certain cytokines during and after isoprinosine treatment, we assigned 10 healthy volunteers to receive isoprinosine 1 g, 3 times daily, 5 consecutive days weekly. Both treatment and follow-up phase last 3 weeks. Interferon-gamma (IFN-gamma), interleukin-2 (IL-2), IL-10, and tumor necrosis factor-alpha (TNF-alpha) were measured in serum using commercial ELISA kits at baseline, 7th, 10th, 14th, 21st, 28th, 35th, and 42nd day. We observed an increase in serum levels of all measured cytokines at 7th to 10th day. The levels of IL-2 had another raise at 42nd day after drop to initial values (P < 0.05; P < 0.001, respectively). Those of IL-10 held up enhanced from 7th to 28th day of measurement (P < 0.01). There was a nearly flat line of values of TNF-alpha after initial slight increase at 10th day. We found a moderate negative correlation between IFN-gamma and IL-2, IL-10, and TNF-alpha (Spearman's r: -0.63, -0.62, -0.63; P < 0.05, respectively). We have demonstrated the immunomodulating properties of isoprinosine in healthy adults. It suggests resumption of the research with up-to-date methods to elucidate the mechanisms of action of inosine pranobex and maybe the other inosine compounds in different clinical settings.

PMID: 20038210
Int J Immunopharmacol. 1991;13(7):1013-8.
Effect of isoprinosine on IL-2, IFN-gamma and IL-4 production in vivo and in vitro.

Milano S, Dieli M, Millott S, Miceli MD, Maltese E, Cillari E.

Institute of General Pathology, University of Palermo, Italy.
Abstract

The effects of an immunopotentiating drug, isoprinosine, on the splenocytes of BALB/c mice to produce cytokines were investigated. Isoprinosine enhanced IL-2 production, upregulating the expression of IL-2 receptor in vitro. It also significantly increased the IFN-gamma secretion and decreased the IL-4 production in vivo. The significance of these findings in terms of immune regulation is discussed.

PMID: 1722191
 

Cort

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Ha! I was already wondering where I could sign up for pills that stimulate APOBEC3 :D

The question is though: is boosting effective for areas that lack this defensive protein?
Actually I don't think we need to boost APOBEC 3 production - I think that enzyme is doing fine to keep the virus from replicating...(If it can do its damage without replicating - that's another story). What researchers will need to find is how to keep it down in cells that are missing that enzyme......
 

Jemal

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I haven't been able to figure out which cells or tissues that is. Anyone??
I find it all very complicated. I have seen APOBEC3 be called an enzym, protein and even a gene. Humans seem to have 7 different families of the APOBEC3 gene. People that have a couple of active APOBEC3 genes seem to be completely immune to HIV infection. HIV has a trick of its own though, it uses a special protein to inactivate APOBEC3. XMRV doesn't know this trick (yet). HIV doesn't always use this trick though, so some people are truly immune to HIV.

It's maddingly difficult to understand... I am guessing at least part of the answer can be found in this study:
http://www.ncbi.nlm.nih.gov/pubmed/19587057
 
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Developing an APOBEC3 mimic could help. The other alternative is to find a drug that can activate the APOBEC3 gene(s) in those cells that don't express the gene(s). Such a drug might help prevent/treat HIV infection as well. If there are multiple varieties of the APOBEC3 gene in most people with most of them inactive, then activating some or all of the varieties (especially in those cells with the least expression) may provide a very effective treatment for XMRV, HIV, and perhaps all forms of human retroviruses.
 

garcia

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I don't think this is unexpected. The APOBEC 3G enzymes beats the heck out of XMRV.
I'm not sure that is always the case.

For example see here:

J Virol. 2010 Oct;84(20):10933-6. Epub 2010 Aug 11.

The glycosylated Gag protein of a murine leukemia virus inhibits the antiretroviral function of APOBEC3.
Kolokithas A, Rosenke K, Malik F, Hendrick D, Swanson L, Santiago ML, Portis JL, Hasenkrug KJ, Evans LH.
Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, Hamilton, MT 59840, USA.

Abstract

APOBEC proteins have evolved as innate defenses against retroviral infections. Human immunodeficiency virus (HIV) encodes the Vif protein to evade human APOBEC3G; however, mouse retroviruses do not encode a Vif homologue, and it has not been understood how they evade mouse APOBEC3. We report here a murine leukemia virus (MuLV) that utilizes its glycosylated Gag protein (gGag) to evade APOBEC3. gGag is critical for infection of in vitro cell lines in the presence of APOBEC3. Furthermore, a gGag-deficient virus restricted for replication in wild-type mice replicates efficiently in APOBEC3 knockout mice, implying a novel role of gGag in circumventing the action of APOBEC3 in vivo.
Source: http://jvi.asm.org/cgi/content/abstract/84/20/10933

[Thanks to Sunshine for finding the above reference]
 

alex3619

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I find it all very complicated. I have seen APOBEC3 be called an enzym, protein and even a gene. Humans seem to have 7 different families of the APOBEC3 gene.
Hi Jemal, maybe this will help. Nearly all enzymes are proteins. All proteins are directly or indirectly made using a gene (via a step involving RNA). So APOBEC3 is most specifically an enzyme unless you are talking about its genetics in which case talking about a gene is more appropriate.
Bye, Alex

ps I hope I am not oversimplifying and stating the obvious because you needed to vent