Back to the Ph.D. thesis. Dr. Biswas tells us, on page 28, “that the tiny percentage of cells that harbor virus are [sic] stably maintained over months or years.” Years?
Could it be maintained for decades, too? Hmmm. At my request, I was tested a few years ago for EBV, but the only thing we found was that I had some anti-EBV antibodies…nothing at all useful…
Anyway, here’s something interesting on page 31: “EBV infects B cells both in vitro and in vivo.” In vitro, EBV makes these B cells immortal. What happens in vivo, however, isn’t that clear. In people who aren’t affected long-term by EBV, as mentioned previously, the virus doesn’t cause any real harm. What triggers it to wake up and initiate the development of different types of cancer?
On page 46 we find “that in myeloma, EBV persists in a latent form in the 47 CD19+CD138- B-cell progenitor population and undergoes lytic reactivation in tandem as the cell becomes a CD19-CD138+ plasma cell.” So something has to happen within the B cell, the CD19 positive cell that is, in order for EBV to wake up and jump into action.
It’s actually on page 46 where my brain almost exploded. Lytic reactivation? 😯 I had absolutely no idea what that meant, so I looked for an “easy” explanation, which I found, finally (if you are interested, have a look here: http://goo.gl/pg8Q6r ).
This study tells us there are two ways in which a virus, nothing more than a “parasite,” can infect its host cell: 1. actively, by causing “a lytic infection characterized by the release of new progeny virus particles, often upon the lysis of the host cell,” (lysis refers to the destruction of a cell, the host cell in this case), or 2. inactively, which occurs when the virus just sleeps, without reproducing itself.
“Reactivation” occurs when a sleeping virus wakes up and reproduces, stimulated by internal or external factors…but that gets into too much detail, so let’s skip that part.
Here’s another clue: in order to be reactivated, EBV needs the help of a protein called Zta, as well as a transcription factor called Rta (remember NF-kappaB?). Not easy to describe a process that I barely comprehend myself, but, in a few words, a transcription factor (XBP-1) activates this pesky Zta, which then rushes over to hug its buddy Rta. The two of them, fortified by their love, then activate other genes, in what is called a “cascade.” (Phew…wiping the sweat off my brow…)
At the end of this process, EBV gets reactivated, which means it’s fully awake and ready to do its evil deeds. And in fact this is discussed in the Ph.D. thesis, too, on page 13, if you want to have a look. Yes, I’m jumping a bit back and forth, but it’s inevitable, especially when things aren’t too clear. [I just hope I’m not making any mistakes…Please correct me if I am! Thanks!]
An important aside (p. 48): EBV doesn’t become a target of T cells because it hides its “viral gene expression during latency.” Aha!!!
Another aside: the EBV myeloma lines are different from those of Burkitt lymphoma and lymphoblastoid cell lines, but are similar to chronic lymphocytic leukemia or CLL cell lines. The EBV-infected CLL B cells, however, do not become immortal and only grow for a short time. Bit of a difference there.
So, okay, back to us: in myeloma, B cells get activated and become plasma cells, thanks to the help of transcription factors (Blimp-1 and the above-mentioned XPB-1, etc.). In this process of transformation, in this cascade of events, EBV disappears. That is, it is no longer present in the newly-created plasma cell. Since plasma cells cannot reproduce themselves, it doesn’t have to be. It has already done its damage.
And now let’s get to something that I thought could be very useful, potentially at least: if you interfere with the cascade, with the process of transformation, EBV cannot reactivate itself.
This is important because, as we can see on page 93, “The investigations presented here show that although the cells that harbor EBV are only a tiny percentage of the cells in culture, EBV is an important driver for the proliferation of the cultured cell population considered as a whole.”
Margaret’s simple (simplistic) solution: we need to block the reactivation of EBV…keep it asleep, like Fluffy, the three-headed dog in Harry Potter. We need to block these transcription factors.
Shortly after I began this umpteenth EBV-MM journey (but, THIS TIME, with PROOF of the association!), I went to see our family doctor, who is a real genius. I’d sent him the main EBV-MM association studies, which we discussed briefly. Then I asked him to prescribe an anti-EBV drug for me.
My idea was: block the EBV = block the MM.
Well (I should have known it), my doctor told me it’s not that simple. Sure, he could prescribe a cycle of acyclovir for me, but:
- For how long?
- What should the dose be?
- Would it work?
- What about the side effects?
- Did I really want to take the risk?
Of course I had no good answers, except to question e. (I’ve taken risks before, so, no biggie). And so I gave up, but only for the time being.
I just have to do some more research. There must be a way, a non-conventional way. Any ideas?
Hmmm, I just read that bortezomib (Velcade) kills EBV. Not that that gives me an incentive to start conventional treatments, mind you! But 1. if you are already on Velcade, AND 2. if EBV might have initiated your myeloma, well then, two birds with one stone, right?
Anyway, proteasome inhibitors in general have an effect against EBV, including, tada!, curcumin.
Food for thought.
Okay, I think I have enough fodder for a Chapter 4, then I’m done with the Ph.D. thesis. Take care, everyone! Ciao!