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标题: [Corrections by Studyforhope] How REP 9AC works. [打印本页]

作者: StephenW 时间: 2011-8-13 17:15 标题: [Corrections by Studyforhope] How REP 9AC works.

I had given some wrong interpretations on this forum about how REP 9AC works to inhibit the entry/exit of HBV. I want to share the explanations, kindly provided to me by Studyforhope on MedHelp, on how REP 9AC actually works. I don't know who Studyforhope is, but to me, he/she is very knowledgeable and I am very grateful to him/her for the explanation.

Your questions:
1.Does REP 9AC block the release/PRODUCTION/FORMATION of spherical and elongated particles(no viral dna and is non-infectious) of HBsAg from infected liver cells?
YES
2.Does REP 9AC block the release of Dane particles from infected liver cells?
NO
3. Or does REP 9AC block the formation of  Dane particles?
NO

The measurement of viral load is done by extrating DNA from the lysed Dane particles. Since the HBv genome is present once per viron, a Dane particle count can be easily calculated from the DNA amount found in the patient serum.

Surface antigen is produced from the HBV cccDNA (circular, closed coiled) by transcription in the nucleus where the cccDNA resides a a minichromosome. The messenger RNA moves to the cytosol for translation and the surface antigen protein is primarily inserted  (HERE IS THE BLOCK BY REPLICOR) in the endoplasmatic reticulum membrane and later processed into vesicles for export.

Dane particle  HBV DNA is synthesized from the progenomic RNA ( made by transcription from the intranuclear permanent cccDNA) inside partially formed cores inside the cystosol, which close by self assembly to a closed sphere while this happens, causing the partial singlestrandedness (incompleteness) of the second so called HBV genomic  plus strand. The cores are later covered with a surface antigen/membranecoat, that is fastened to the core by inward directed preS1 loops, while the outward, myristylated preS1 loops of the Dane particles are the ones that make later  (after release of the virion from the hepatozyte into the circulation) contact for infection to the targeted  liver cell membrane receptor, causing entry to the hepatozyte. When an artificillay introduced pres1  peptide molecule is already stuck on these receptors (importantly, a small receptor percentage is enough to block!!!) (HERE IS THE BLOCK BY MYRCLUDEX!) then the Dane particle membrane cannot get close enough to the cell membrane to FUSE, thus NO ENTRY, no reinfection, a cleaner liver, day by day....

作者: tonychant 时间: 2011-8-13 19:11

can you speak chinese?

作者: StephenW 时间: 2011-8-13 20:37

tonychant 发表于 2011-8-13 19:11
can you speak chinese?

Yes, I can read but not write (except by using Google Translate). Why ask?

作者: 灰天 时间: 2011-8-13 21:02

那就帮忙GOOGLE一下嘛

作者: StephenW 时间: 2011-8-13 21:27

本帖最后由 StephenW 于 2011-8-13 21:28 编辑

回复灰天的帖子

论坛上,我给了REP 9AC如何抑制HBV的进入/退出一些错误的解释。我想分享，由Studyforhope提供REP 9AC如何实际工作的解释，。我不知道Studyforhope是谁，但对我来说，他/她是很熟悉REP 9AC，我非常感谢他/她的解释。

您的问题：
1.Does REP 9AC 阻止球形和片状形颗粒的乙肝表面抗原
颗粒（没有病毒DNA和非感染性)的释放/生产/形成？
YES
2. REP 9AC阻止感染的肝细胞释放Dane颗粒？
不是
3。 REP 9AC阻止Dane颗粒的形成？
不是

病毒载量的测量是通过extracting从裂解Dane颗粒的DNA。由于HBV基因组是目前每virion一次，一个丹麦的粒子计数可以很容易地计算出在病人血清中发现的DNA量。
表面抗原是从乙肝病毒cccDNA的（圆形，封闭盘绕）的转录在细胞核内的cccDNA的驻留AA minichromosome。的信使RNA转移到细胞质的翻译，是主要的表面抗原蛋白插入（这里是由REPLICOR阻止）endoplasmatic网膜，后加工成出口囊泡。
丹麦颗粒乙型肝炎病毒DNA合成的progenomic RNA（通过从细胞核内永久的cccDNA的转录）内的部分内cystosol形成核心，关闭自组装到一个封闭的领域，而发生这种情况，造成部分singlestrandedness（不完备的）第二个所谓的乙肝病毒基因组正链。内核表面抗原/ membrane coat外来指示前S1循环的核心，就是固定后覆盖，而向外，myristylated前S1的Dane颗粒的循环使后来的（后释放的病毒颗粒从hepatozyte进入流通领域）接触感染的有针对性的肝细胞膜受体，造成进入的hepatozyte。当一个artificially推出前S1蛋白肽分子是已经坚持对这些受体（重要的是，一个小受体的比例是足以阻止！！！）（这按MYRCLUDEX阻止！），然后在丹麦颗粒膜能不能得到足够接近到细胞膜熔断，从而没有进入，没有再感染，清洁肝，一天一天....

作者: StephenW 时间: 2011-8-13 21:37

[attach]233159[/attach]

作者: 灰天 时间: 2011-8-13 21:40

谢谢你能够把这些信息给我们分享

作者: StephenW 时间: 2011-8-14 15:09

Further clarification from Studyforhope:

NO. REPLICOR IS NOT AN ENTRY INHIBITOR FOR HBV. IT IS FOR INFLUENZA, HCV AND HIV, BUT NOT FOR HBV.

作者: 灰天 时间: 2011-8-15 21:28

hbsag>250,hbsab8.9,e抗原0.46，e抗体0.04.核心抗体9.9，IGM0.1,肝功基本正常，b超正常，dna正常.....什么情况（多年小三阳携带）能帮我看看吗

作者: 灰天 时间: 2011-8-15 21:29

hbsag>250,hbsab8.9,e抗原0.46，e抗体0.04.核心抗体9.9，IGM0.1,肝功基本正常，b超正常，dna正常.....什么情况（多年小三阳携带）.帮我看看

作者: StephenW 时间: 2011-8-15 23:23

本帖最后由 StephenW 于 2011-8-15 23:24 编辑

灰天发表于 2011-8-15 21:29
hbsag>250,hbsab8.9,e抗原0.46，e抗体0.04.核心抗体9.9，IGM0.1,肝功基本正常，b超正常，dna正常.....什么 ...

我不是专家，我给你我个人的意见。
通常情况下，乙肝表面抗体需将超过10才有意义的。
我建议在几个月后你再次测试您的乙肝表面抗原和乙肝表面抗体。
重要的是肝功正常, dna ~ 0.

作者: 灰天 时间: 2011-8-16 12:21

谢谢

作者: StephenW 时间: 2011-8-16 15:48

Some more explanations from studyforhope. [UND - I think it means undetectable]

1. REP 9AC is best used with an antiviral (that reduces viral load and thus re-infection)?

A difficult question, because a reduction in viral load by the antiviral is also often followed by lower immune activity, that might delay the reawakening of the immune response to the surface antigen after it has been blocked by REp9AC from flooding the system.
Nevertheless, the capacity of HBV to grow back against the reawakened surface epitope Tcell mediated clearance effect should be much weaker with an antiviral in place. HBV is a dynamic disease and the dramatic reduction by antivirals of the replicative capacity of  HBV should help the clearance dynamics.

The blockage of reinfection by antivirals might not be as effective as one might think. The virus overproduces virions tens of thousandfold over the amount needed to fully reinfect. Not only is the UND status misleading insofar as the detection methods still have limited sensitivity and UND could still mean a production of eg 50000 dane particles a day, but yet another critical effect has to be considered. Freshly produced virions in particular will readily infect a neighboring hepatocyte cell from the space of Disse, but also circulating virions will be rapidly absorbed and removed by the liver by its affinity to the preS1myr  binding receptor at the hepatocyte surface. To put it simple, the liver will act like a gigantic affinity absorbing column/mass, removing/ clearing Dane particles from the circulation until it is saturated. Thus even real UND with more sensitive methods might not mean that there is still a large amount of reinfection/remnant virion production  going on.

2. REP 9AC is best used with an entry inhibitor like Myrcludex?
This could be an ideal combination, because any freshly produced or cleared cell will be protected from reinfection, allowing slow but consistent reduction of viral infestation of the liver.
Here is however another critical argument regarding the replacement of immune cleared cells by fresh uninfected hepatocytes; While the mainstream thinking is that hepatocytes are replaced by division from so called satellite cells embedded in the liver ( 'liver stem cells") others think that regular hepatocytes will divide once the regnerative impulse/signal  from Hepatocyte Growth Factor is sensed to replace a shrinking liver mass. The dividing "mother" cell is likely infected, and since there are typically 10 to 30 HBV cccDNA molecules in the nucleus, these will be distributed into the daughter cells, which then, bingo, are already infected from their "birth".
Antivirals typically reduce the amount of cccDNA, but nor dramatically, at best about 10 times.This might still help in this scenario.

3. REP 9AC, by reducing the number of HBsAg particles, is sufficient to allow the immune system to do its job in clearing hbv?

This will depend on the vigor and breath of the anti surface Tcell  (cd8 - cytotoxic/killer as well as cd4 helper Tcells) and later B cell response. It has been tolerized by oversupply with antigen for a long time, most clones will be exhausted or lost. Thus a less than perfect SVR rate can be explained by an insuffcient recovery of that system. It will take time to regenerate, reawake, possibly by the novo supply from the thymus. Some think that the surface antigen mainly acted as a suppressor of innate immunity, that this innate immunity will restart once the mitigating protein hasd disappeared from the circulation. Chisari and the majority of HBV immunology specialist place more emphasis on the adaptive, specific response, since it allows targeted removal of HBV protein producing infected cells. In reality, innate immunity is the danger sensing promotor of adaptive imunity, the two work in intimate collaboration and therefore both need to be quite functional for a successful clearance event.

4. What is the method used to deliver REP 9AC into the liver cells?
From what was  heard at the European meeting, it is by weekly infusion.

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