主题：警惕禽流感武器 -- 唵啊吽

Yes.

In general influenza A virus consists of 8 genes. Influenza virus evolves to be able to adapt to new host. The evolution can happen in several way: by exchanging one or more complete genes (for example avian virus switching gene with human virus), called as reassortment; or only changing partial gene(s), called as recombination.

In the case of novel H1N1, this virus consists 8 genes mixed of avian, swine and human type influenza A virus. So, this is a reassortant virus.

Adaptation can occur too. This means, the virus makes small change (sometime only one amino acid change) but can make a complete adaptation to the new host. For example, if we passage human virus into eggs, the virus will make small mutation after several passage and will be reach efficiency to infect eggs (means, able to infect new host, in this case avian host). This is why Adrian Gibbs once said that novel H1N1 was a lab strain. Because he found a specific amino acid which might refer to the consequence of several passage in eggs. Vaccine industry usually amplify virus by isolating it into eggs, and after several passages this mutation can be found.

Mutation takes time to occur, up to the rate of amino acid substitution. For example, for HA gene, duck virus' HA has substitution rate about 3 x 10e-4 per site per year which is slower compare to human and swine HA (about 10e-3 per site per year). If total nucleotide number in influenza A virus HA is 1,700, then it takes 3 years for making single changes in duck virus, or 1.7 year in the case of human and swine virus. In instance, a complete gene mutation can take thousand of years to be established.

I read a paper of Suzuki and Nei, 2002 (Mol. Biol.Evol. 19(4): 501-509 2002), they mentioned that the divergence between subtypes of influenza A virus HA genes was estimated to be about 2000 years ago.

It means, duck virus (as well as other waterfowls) tends stable compare to human and swine virus. Well, waterfowls are the natural host of influenza virus, so it's more constant. But when the virus jumps into new host (like chickens, pigs or human), the substitution rate will accelerate to adapt well in the new host. New adaptation will cause rapid mutation, but it will be slowing down after time. We see the same pattern in the case of novel H1N1. The novel H1N1 shows stable sequences since its first outbreak. Usually I compare the later sequence with first California sequence, and in general the virus is quiet stable. Some important mutations are detected, though. Such as, amino acid no 627 of PB2 gene, which is related to mammalian adapted strain, found in a Shanghai isolate. Also, a mutation in amino acid no 275 of NA gene, which is related to oseltamivir resistant strain, were found in one Canada and one Japan isolates. Some other 'silent' mutations (silent means no amino acid changes) can be found in other isolates, but still I think that the virus is quiet stable up to now.

Now I'm talking about the reassortment (like novel H1N1 virus). It may take shorter time to occur compare to amino acid substitution/adaptation/mutation. If you take a look to the genotype map and the phylogenetic trees that I sent you previously, the novel H1N1 virus consists of avian, human and swine virus genes. The theory is maybe an individu got infected by avian, human and swine virus at the same time, and the viruses exchanged genes inside the body, creating a new virus having mixed genes and spreading. Theoritically it is possible to occur. But how?

What we need:

a. A host. The host should have efficient receptor for those three different derived hosts. So far, human virus tends to infect human, because it suits to human receptor. Avian virus tends to infect birds, because it suits to bird receptors. Pigs have both human and avian type receptors, so it is said that pig is the 'mixing vessel'. However, some researchers tried to prove this mixing vessel theory by trying to infect pigs by human and avian viruses to create reassortant. They didn't make it.

There are some reports that showed the finding of human and bird influenza virus in pigs. So it is easy for pigs to get infected by human and birds, but lack of report showing that pigs shed the reassortant virus and infect new host.

So,where is the responsible host? The first novel H1N1 virus was found in human. After that what I know is some pigs and turkey were transmitted this virus by farm workers. Not the opposite. Until now, no one can give evidence of this reassortant theory.

b. Reassortant needs ancestor viruses

Aain, if you check the phylogenetic tree. It shows, the NA and M genes derived from avian virus; PB1 from human H3N2; other genes (PB2, PA, HA, NP, NS) from swine triple reassortant, Swine H1N2 and Eurasian Swine (H1N1/H3N2). The triple reassortant swine I mentioned before, actually derived from human H3N2 which infected pigs, and has been circulating in North America at least for 20 years.So that people say it as swine virus (well, I'm still saying it's actually human virus).

Funny thing is those suspected ancestors are coming from pretty old isolates.

A paper written by Smith et al., 2009, is saying that the NA gene comes from 1996-2001 isolate (I suspect this as the NA gene of H5N1, the isolate year confirmed this). The M genes from 1990-1993 isolates, the others even pretty old, somewhere between 1979 to 80's isolates. The author argued that the virus had been detected for over 20 years without being detected???

Come on, people is doing surveillance everywhere, but no one detected the virus for 20 years??

A reassortant can happen very quick. If it was already there before, it must have been spreading long time ago, is it in pigs or human or else.

But again where's the evidence??

Still they said the virus is circulating in pigs, but no one can prove it.

We can make a story about this: there is a pig, got infected by human and avian virus from 10 to 20 years ago isolates. And creating a very good virus with effective transmissibility. Please, how can you find those pretty old isolates circulating?? Doesn't make sense.

c. Reassortant needs to be facilitated.

Now tell me Robert. How can you mix avian, human and pig virus at one time? The viruses must come from Europe, America and Asia, without being noticed? And luckily you can make completely efficient newly generated virus?

Simply for me, the virus was emerged suddenly in Mexico. I can't explain how. I wish I could. For me as a virologist, it's impossible. In the other hand, technology can create any kind of virus you want.

和所有“国际型”美国佬一样，迈格尔看上去热情，健谈，不拘小节，喜欢争论、装酷。当然，这些都是表象，在新疆、广东游玩期间，我发现他还有着另外一些捉摸不透的性格，比如突然变得阴冷，或者焦躁，有几次居然把我们扔在宾馆，自己独自出去“游山玩水”，几天不见人影。这些奇怪的，事后也没有得到额外解释的举动，让我隐隐约约感觉到，他可能有着更神秘的身份。

但是，他是老板特别关照要礼貌招待的客人，所以我和翻译虽然有些狐疑，也装着视而不见，倒是他自己最后忍不住——也许是良心发现，也许我们几个月相处，确实结下了让他感动的友谊——用一种无法作为证据的方式显露自己其实有着另外的特殊身份。

某天，确切地说是2002年10月中旬，在他决定离开中国返回美国的那个傍晚，我们在一家咖啡馆做告别聚餐的时候，他不由分说、以命令的口气要我和翻译尽快离开广州。翻译本来就是北京人，当然会回去，彼时，也恰好有朋友邀请我去北方发展，我已为这个提议犹豫了好几个月，于是也鬼使神差地听从了他的劝告，去了北方。

半个月后，是的，仅仅只是半个月后，一种通过呼吸道传染的、足以让人致命的病毒，开始在广州蔓延（注释：2002年11月开始，广州附近市镇出现一种通过空气快速传播的致命新病毒，该病毒在侵入人体后，可自己进行复制，引起机体的异常免疫反应，直接损伤免疫系统特别是淋巴细胞，感染者的死亡率高达11%，广州、北京很快成为这种那个病毒的重灾区，感染人数迅速上升，该病毒还通过香港、澳门，被传向了台湾、新加坡、欧洲、北美等地，2003年1月22日，中国大陆首次使用“非典型肺炎”来对它命名，2月底，世界卫生组织意大利籍传染病专家卡洛·厄巴尼（Carlo Urbani）大夫根据当时已经掌握的情况，将其命名为severe acute respiratory syndrome，简称SARS。整个非典期间，中国大陆有数千人被感染，330余人死亡。）……记得最初得知这个消息时，我刚在新单位办完入职手续，完全惊呆了，迈格尔那番明显充满画外音的话，再一次在我耳边响起，这段话实在太特别了，乃至直到今天，我依然能几乎一字不漏地背出来——“有些事情，不是你能阻止，也不是我能阻止，而是，它必须发生，卡（注：为方便旅途交流我特意取的英文名），相信我，你和罗斯（注：翻译）一定要离开这里，走的越远越好，否则，你们会很快发现，自己做了一个糟糕的决定，非常的糟糕，我与你们相处这几个月，我已在心里把你们当做了我很好的朋友了，它迫使我离开前必须对你们说这些话，相信我，我是值得你们信赖的朋友，我的劝告没有恶意”。

迈格尔说这番话时，脸上带着一股不容质疑的严肃，也许，还有隐约的内疚，乃至惶恐，这让他本来英俊的脸看上去有些古怪，让人本能地感到这番话不同寻常，至少，我脊背当时就突然变得凉飕飕的。

在证实广州确实发生了疫情，并正在扩大之后，我本能地觉得，“热爱中国文化的游客”迈格尔，一定与这次突然发生的疫情有某种神秘的联系，

和所有“国际型”美国佬一样，迈格尔看上去热情，健谈，不拘小节，喜欢争论、装酷。当然，这些都是表象，在新疆、广东游玩期间，我发现他还有着另外一些捉摸不透的性格，比如突然变得阴冷，或者焦躁，有几次居然把我们扔在宾馆，自己独自出去“游山玩水”，几天不见人影。这些奇怪的，事后也没有得到额外解释的举动，让我隐隐约约感觉到，他可能有着更神秘的身份。

但是，他是老板特别关照要礼貌招待的客人，所以我和翻译虽然有些狐疑，也装着视而不见，倒是他自己最后忍不住——也许是良心发现，也许我们几个月相处，确实结下了让他感动的友谊——用一种无法作为证据的方式显露自己其实有着另外的特殊身份。

某天，确切地说是2002年10月中旬，在他决定离开中国返回美国的那个傍晚，我们在一家咖啡馆做告别聚餐的时候，他不由分说、以命令的口气要我和翻译尽快离开广州。翻译本来就是北京人，当然会回去，彼时，也恰好有朋友邀请我去北方发展，我已为这个提议犹豫了好几个月，于是也鬼使神差地听从了他的劝告，去了北方。

半个月后，是的，仅仅只是半个月后，一种通过呼吸道传染的、足以让人致命的病毒，开始在广州蔓延（注释：2002年11月开始，广州附近市镇出现一种通过空气快速传播的致命新病毒，该病毒在侵入人体后，可自己进行复制，引起机体的异常免疫反应，直接损伤免疫系统特别是淋巴细胞，感染者的死亡率高达11%，广州、北京很快成为这种那个病毒的重灾区，感染人数迅速上升，该病毒还通过香港、澳门，被传向了台湾、新加坡、欧洲、北美等地，2003年1月22日，中国大陆首次使用“非典型肺炎”来对它命名，2月底，世界卫生组织意大利籍传染病专家卡洛·厄巴尼（Carlo Urbani）大夫根据当时已经掌握的情况，将其命名为severe acute respiratory syndrome，简称SARS。整个非典期间，中国大陆有数千人被感染，330余人死亡。）……记得最初得知这个消息时，我刚在新单位办完入职手续，完全惊呆了，迈格尔那番明显充满画外音的话，再一次在我耳边响起，这段话实在太特别了，乃至直到今天，我依然能几乎一字不漏地背出来——“有些事情，不是你能阻止，也不是我能阻止，而是，它必须发生，卡（注：为方便旅途交流我特意取的英文名），相信我，你和罗斯（注：翻译）一定要离开这里，走的越远越好，否则，你们会很快发现，自己做了一个糟糕的决定，非常的糟糕，我与你们相处这几个月，我已在心里把你们当做了我很好的朋友了，它迫使我离开前必须对你们说这些话，相信我，我是值得你们信赖的朋友，我的劝告没有恶意”。

迈格尔说这番话时，脸上带着一股不容质疑的严肃，也许，还有隐约的内疚，乃至惶恐，这让他本来英俊的脸看上去有些古怪，让人本能地感到这番话不同寻常，至少，我脊背当时就突然变得凉飕飕的。

在证实广州确实发生了疫情，并正在扩大之后，我本能地觉得，“热爱中国文化的游客”迈格尔，一定与这次突然发生的疫情有某种神秘的联系，