Example entry: How the virus stays in the liver and what it does there

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My lab is interested in finding out how the virus stays in the liver for so long and what it does when it’s there.

The most stable form of the virus is its DNA because it’s very similar to our own DNA. If you think about your own DNA, you have it in each one of your cells for your entire life. It is super-stable and the virus mimics this.

There actually 2 different types of stable virus DNA and my group looks at both of them:

1) cccDNA - covalently closed circular DNA.
This is one you probably know of. If a cell has this form, it can easily produce new viruses; it’s basically a virus blueprint. The current drugs (Entecavir/Viread/Vemlidy) don’t actually target this blueprint, just the manufacturing of new viruses.

My group is looking at what the cell can do to get rid of it. One way that we’ve shown is just by dividing: if a cell splits, then our data suggests that the cccDNA is gone in the 2 cells that result. We’re now trying to understand why some cccDNA persists, even though the liver cells undergo a lot of division.

If we can understand these sorts of very basic ways that the cccDNA hangs around, then we will know exactly how to target it and hopefully get rid of the virus completely. This would mean a “complete cure”: you wouldn’t have to take medications for such a long time and there wouldn’t be a risk of the virus reactivating (there would be nothing to reactivate it from).

2) Integrated virus DNA
I’ve been working on super-interesting form of the virus since the very start of my career and it’s still puzzling scientists. Instead of making cccDNA, very rarely (1 in 10000 cells) the virus can jump into our own DNA. When it does this, it loses part of itself and it can’t produce new virus anymore. So why does the virus do this? We don’t know! (and whenever we don’t know, scientists get really interested).

What becomes important to human health is that even though it happens very rarely, it’s very commonly in liver cancers (most liver cancers have integrated virus DNA). So our research is trying to figure out why this is.

We’ve looked at if the integration itself causes cancer. My studies have shown that integration happens within days of an infection, but it takes many many decades for liver cancer to happen. So it doesn’t look like just because you have integration it directly causes cancer.

We think it might be something like integrations happen in cells that are more likely to become cancer (like if you have broken DNA, you are more likely to have integrations but also more likely to get cancer), though this is all very preliminary.

But it is important. If we understand what is actually driving liver cancer, we can develop ways to prevent it. Hep B is probably one of the better conditions for this cancer prevention to work, because the Hep B is easy to diagnose (blood test panels) and many times you have decades to intervene before cancer comes about.

Happy to take any questions about my research!
TT

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This is the simplest &easiest way to understand and explain healthcare provider about the behavior of HBV. Good & excellent explanation.Dr.Thomas Tu.
In my opinion, I compare the lifecycle of this virus with the bee Life cycle . The cccDNA is like the queen,it can produce pregenomic RNA to form viruses like the drone , subgenomic RNA to translate in structural protein eg. HbsAg,HBeAg like the honey bee jelly but it is poisonous.
Dr.Chulapong Chanta
Asst prof at MEC Chiangrai hospital .Thailand.

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Thank you for your kind words, @chul_chan! I’m glad the explanation could be helpful.

TT

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Hi Thomas,

Thank you for taking the time to write about your work. It’s comforting for me to know that it is one aspect of the virus that needs to be more heavily focused on for cure research, to be able to see exactly what research is being conducted, as well as its findings at a glance. It helps to make all the big, and often intimidating sciency words make sense, and help prevent me at least, from falling into the modern-age trap of going down what I like to call the “Google rabbit-hole of doom”

Being able to understand the ins and outs of how HBV works in my body is a key way for me to process what is happening to me. When I got my diagnosis and saw the increased risk of liver disease and liver cancer well, that was it, the Big C was mentioned and of course, me being me, I started panicking so it’s good to know that there is a long period between HBV infection and liver cancer (usually).

It’s thanks to the efforts of everyone in the scientific community as well as yourself in creating this community that there is a space for this information to be freely distributed and easily digested by the very people your research is aiming to assist.

My sincere thanks for your hard work. :heart:

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Thank you so much for the kind words, @EH1999. This is exactly what I was looking to do by launching the research showcase, so your post has made me extremely happy. I’m so so glad that this community (that is really built by all of its members, not me) has helped you.

Thomas

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Hi Thomas,
Thanks for sharing this and make it very easy to understand, this inspired me to ask some noob questions…

once one get infected, does it mean that all liver cells are infected with the virus, even if they developed immunity as it takes the immune system up to 6 months to develop adequate antibodies in case natural immunity is reached?

send question, does this integrated virus DNA form present in all infected people in this case?

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Thanks for the questions, @moe.

This is the current thinking, yes. Even in acute infection, we think that almost all of the liver cells are HBV-positive.

Yes, various animal models of HBV and some clinical data shows that integrated HBV DNA remains in everyone exposed to the virus, even in people who have cleared the virus (become HBsAg-negative).

Thomas

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Dear @ThomasTu ,
Thank you for your great work and for your help to us infected falks out there!
I have a good story to tell and a couple of questions to ask.
I am 42 and I had chronic HBV infection from age of 3 or 4 (infected with poorly boiled syringe probably). After graduation fom university almost 20 years ago I tried treatment with interferon-alpha for 6 months but it did not help. Instead I developped a lot of really bad side-effects of interferon like massive hair loss and others. In the past few years I started doing Yoga once a week and started what I would call “intuitive food taking”. In December 2022 I took my usual boold tests for all major HBV markers and to my surprise I found that I became HBsAg negative for the first time in my life! Also I had negative HBV DNA by PCR method and positive anti-HBsAg, and positive anti-HBe. This is great. I gues it is called resolved HBV or occult HBV (which is right?) and overall forecast is good in this case.
But as I understand some HBV DNA is going to present in liver cells still. So now I wonder:

  1. Will have the viral DNA inside liver cells for life OR is it possible (and what are the chances) that all my cells will become completely free of viral DNA?
  2. I heard of cases (maybe it is not true) where virus mutated to such extent that standard tests may start showing HBsAg negative. Can it possibly be my case? Or is it possible at all?
    THANK YOU VERY MUCH IN ADVANCE : )
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Welcome to the forum, @Eastwood37. Thanks for sharing your story and the interesting questions.

For people who have cleared HBV (become HBsAg negative), the liver still contains cccDNA and integrated DNA. We still don’t understand if the liver will eventually clear it over many years or not because there are no good tests to detect this DNA without liver biopsy. Given it is very difficult to justify a liver biopsy in someone who is otherwise healthy, this remains something hard to research.

This could be possible, but it is very unlikely in your case given your HBV DNA test is negative. If there was such a resistance, then HBV DNA would be detectable.

Hope this helps,
Thomas

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Wow! This is such a positive news! I hope something like this happens to my husband too.

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