Inefficient Transmission of H5N1 Influenza Viruses in a Ferret Contact Mode

[Anne]

[SIZE=-1]http://jvi.asm.org/cgi/content/abstract/81/13/6890

Journal of Virology, July 2007, p. 6890-6898, Vol. 81, No. 13
0022-538X/07/$08.00+0 doi:10.1128/JVI.00170-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.[/SIZE]
Inefficient Transmission of H5N1 Influenza Viruses in a Ferret Contact Model<sup>

</sup>

Hui-Ling Yen,¹ Aleksandr S. Lipatov,¹^,¶ Natalia A. Ilyushina,¹ Elena A. Govorkova,¹ John Franks,¹ Neziha Yilmaz,² Alan Douglas,³ Alan Hay,³ Scott Krauss,¹ Jerold E. Rehg,⁴ Erich Hoffmann,¹ and Robert G. Webster¹^* Departments of Infectious Diseases (Division of Virology),¹ Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee,⁴ Department of Virology, Refik Saydam Hygiene Institute, Sihhiye-Ankara, Turkey,² Division of Virology, National Institute for Medical Research, London, United Kingdom³
Received 25 January 2007/ Accepted 16 April 2007
<!-- ABS --> The abilities to infect and transmit efficiently among humansare essential for a novel influenza A virus to cause a pandemic.To evaluate the pandemic potential of widely disseminated H5N1influenza viruses, a ferret contact model using experimentalgroups comprised of one inoculated ferret and two contact ferretswas used to study the transmissibility of four human H5N1 virusesisolated from 2003 to 2006. The effects of viral pathogenicityand receptor binding specificity (affinity to synthetic sialosaccharideswith

2,3 or

2,6 linkages) on transmissibility were assessed.A/Vietnam/1203/04 and A/Vietnam/JP36-2/05 viruses, which possess"avian-like"

2,3-linked sialic acid (SA) receptor specificity,caused neurological symptoms and death in ferrets inoculatedwith 10³ 50% tissue culture infectious doses. A/Hong Kong/213/03and A/Turkey/65-596/06 viruses, which show binding affinityfor "human-like"

2,6-linked SA receptors in addition to theiraffinity for

2,3-linked SA receptors, caused mild clinical symptomsand were not lethal to the ferrets. No transmission of A/Vietnam/1203/04or A/Turkey/65-596/06 virus was detected. One contact ferretdeveloped neutralizing antibodies to A/Hong Kong/213/03 butdid not exhibit any clinical signs or detectable virus shedding.In two groups, one of two naïve contact ferrets had detectablevirus after 6 to 8 days when housed together with the A/Vietnam/JP36-2/05virus-inoculated ferrets. Infected contact ferrets showed severeclinical signs, although little or no virus was detected innasal washes. This limited virus shedding explained the absenceof secondary transmission from the infected contact ferret tothe other naïve ferret that were housed together. Our resultssuggest that despite their receptor binding affinity, circulatingH5N1 viruses retain molecular determinants that restrict theirspread among mammalian species.

<hr align="left" width="50%"><!-- null --> * Corresponding author. Mailing address: Department of Infectious Diseases, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105. Phone: (901) 495-3400. E-mail: robert.webster@stjude.org

 

[gsgs]

Re: Inefficient Transmission of H5N1 Influenza Viruses in a Ferret Contact Mode

thanks.
Now, please, implement these changes at the RBD : S227N or
186+196 and test how those viruses transmit !

 

[HenryN]

Re: Inefficient Transmission of H5N1 Influenza Viruses in a Ferret Contact Mode

thanks.
Now, please, implement these changes at the RBD : S227N or
186+196 and test how those viruses transmit !

The isolates from Turkey and Hong Kong have S227N (and the original papers on S227N showed that affinity for mammalian receptos was increased and avian decreased, but the affinity was still well below that of seasonal flu). This is yet another experiment where the devil is in the details, and based upon the abstract, those details were ignored.

Yet another "feel good" paper by WHO consultants..

 

[HenryN]

Re: Inefficient Transmission of H5N1 Influenza Viruses in a Ferret Contact Mode

Details:

http://www.ncbi.nlm.nih.gov/entrez/...ve&db=PubMed&list_uids=16226289&dopt=Abstract

1: Virology. 2006 Jan 20;344(2):432-8. Epub 2005 Oct 13. Cited in PMC, LinkOut

<DD class=abstract id=abstract16226289>Evolution of the receptor binding phenotype of influenza A (H5) viruses.

• Gambaryan A,
• Tuzikov A,
• Pazynina G,
• Bovin N,
• Balish A,
• Klimov A.

Chumakov Institute of Poliomyelitis and Viral Encephalitides, Russian Academy of Medical Sciences, 142782 Moscow, Russia. gambar@com2com.ru
Receptor specificity of influenza A/H5 viruses including human 2003-04 isolates was studied. All but two isolates preserved high affinity to Sia2-3Gal (avian-like) receptors. However, two isolates (February, 2003, Hong Kong) demonstrated decreased affinity to Sia2-3Gal and moderate affinity to a Sia2-6Gal (human-like) receptors. These two viruses had a unique Ser227-Asn change in the hemagglutinin molecule. Thus, a single amino acid substitution can significantly alter receptor specificity of avian H5N1 viruses, providing them with an ability to bind to receptors optimal for human influenza viruses. Asian 2003-04 H5 isolates from chickens and humans demonstrated highest affinity to the sulfated trisaccharide Neu5Acalpha2-3Galbeta1-4(6-HSO3)GlcNAcbeta (Su-3'SLN) receptor but, in contrast to 1997 isolates, had increased affinity to fucosylated Su-3'SLN. American poultry H5 viruses also had increased affinity to Su-3'SLN. These data demonstrate that the genetic evolution of avian influenza A(H5N1) viruses is accompanied during adaptation to poultry by the evolution of their receptor specificity.
PMID: 16226289 [PubMed - indexed for MEDLINE]

</DD>

 

[HenryN]

Re: Inefficient Transmission of H5N1 Influenza Viruses in a Ferret Contact Mode

To put these data into easily undestood language, the S227N change makes it easier for H5N1 to infect humans by allowing the virus to more efficiently attach to human cells in the upper respiratory tract. However, this ability has a quatitative component, so although it is easier, it is not as easy as seasonal flu, which is efficiently trabsmitted.

Thus, in non-quantitative assays that measure weak binding, the S227N can be shown to allow binding. As seen in Turkey, S227N, was linked to family clusters (and the first reported human case involving the Qinghai strain). As seen in Egypt, S227N was linked to a geographical cluster (El Sharik). However, this was not sufficient to allow for the type of spread seen for seasonal flu.

Thus, changing a single amino acid can move H5N1 toward a pandemic strain, but that one change is not quite enough.

 

[JJackson]

Re: Inefficient Transmission of H5N1 Influenza Viruses in a Ferret Contact Mode

Henry, I am not sure how 'feel good' that abstract is. I dont have access to the whole paper but my take on it is. The S227N mutation confers adequate, but not perfect, mamalian binding but we think there is some other block to efficient spread and we dont know what (or where) it is. That being the case then we have no idea which sequence changes (or change) would be required to remove that block and release the log jam. I don't feel all that good.

 

[HenryN]

Re: Inefficient Transmission of H5N1 Influenza Viruses in a Ferret Contact Mode

Henry, I am not sure how 'feel good' that abstract is. I dont have access to the whole paper but my take on it is. The S227N mutation confers adequate, but not perfect, mamalian binding but we think there is some other block to efficient spread and we dont know what (or where) it is. That being the case then we have no idea which sequence changes (or change) would be required to remove that block and release the log jam. I don't feel all that good.

There is no evidence for a block elsewhere. If "adequate" was "excellent", there would be a pandemic.

 

[Anne]

Re: Inefficient Transmission of H5N1 Influenza Viruses in a Ferret Contact Mode

you must keep in mind : polymerases, NS1, etc..

the 1918 virus was not really adequat for human, at the binding site.

 

[Mamabird]

Re: Inefficient Transmission of H5N1 Influenza Viruses in a Ferret Contact Mode

you must keep in mind : polymerases, NS1, etc..

the 1918 virus was not really adequat for human, at the binding site.

I must respectfully challenge this. Brevig Mission had all of the following RBD area mutations that changed its characteristics from avian to human: E190D, S221P, N224R, G225D and F233Y.

Your H1N1 and H3N2 seasonal viruses all have the above characteristics as well, while the H5N1 viruses do not. The 1918 virus was very well adapted to alpha 2,6 linkages. If you see any of the above mutations in H5 or H7 avian viruses, you can bet they are moving toward human adaptation.

 

[JJackson]

Re: Inefficient Transmission of H5N1 Influenza Viruses in a Ferret Contact Mode

In November 2006 Jeffery Taubenberger gave a talk (can bee see here but you will need to seach on his name as it has dropped off the 'recent' list http://www.videocast.nih.gov/PastEvents.asp?c=998) in which he said he and his assosiates were trying to recover more sequences of H1N1 from the panademic and pre-pandemic period. I thought this would be very interesting if they enabled us to view either the the pre-pandemic virus as it edged to its pandemic form or the newly pandemic form as it continued to evolve and adapt to its new host. However since then I have not seen anything published and wondered if anyone else had?

 

[Mamabird]

Re: Inefficient Transmission of H5N1 Influenza Viruses in a Ferret Contact Mode

trying to recover more sequences of H1N1 from the panademic and pre-pandemic period. I have not seen anything published and wondered if anyone else had?

I too have not seen any recent information of the status of this interesting research. As I recall, all of the subject hosts were from the UK.

 

[HenryN]

Re: Inefficient Transmission of H5N1 Influenza Viruses in a Ferret Contact Mode

you must keep in mind : polymerases, NS1, etc..

the 1918 virus was not really adequat for human, at the binding site.

1918 was a human H1N1 / swine H1N1 recombinant. Receptor binding was not a problem. It was almost all mammalian (and 1918 matched both human and swine H1N1 at the "critical" 10 polymerase positions).

There is NO data on a 1917 human or swine sequences and the changes betwen mammalian and avian were not new in 1918 and are not new now.

 

[Anne]

Re: Inefficient Transmission of H5N1 Influenza Viruses in a Ferret Contact Mode

jjakson : the video posed much questions.
I watch impatiently for the publication, the video was in november.. so,I presume that we must wait about one year

 

[JJackson]

Re: Inefficient Transmission of H5N1 Influenza Viruses in a Ferret Contact Mode

A few points from the above.

Regardless of the mechanism of H1N1 – or H5N1 – reaching a pandemic form it is a zoonotics emergence and therefore the virus and host species need to adapt to each other. As humans are complex organisms with long generational times our adaptations are immunological (development of individual & herd immunity), behavioural (reduced social interaction) and uniquely to humans technological (we will research vaccines & antivirals). The virus’ response to its new host will be evolutionary with selection pressure promoting strains with sequence changes that confer some advantage be it a degree of antiviral resistance, adaptation to replication at the lower temperatures of the nasopharynx or efficient binding etc. As discussed above we are now seeing sequence changes in H5N1 and are aware of the significance of some of them to species adaptation but thankful are not yet in a position to view those changes that occur after a pandemic starts. Due to the paucity of data on H1N1 sequences at present we are unable to track the changes in H1N1 either pre or post case Zero. As the pandemic did not reach Brevig Mission until it had already cycled main times in a human host the genetic snapshot from the body exhumed form the permafrost is for a well adapted virus. If Taubenberger et al can generate more sequences we may be able to piece together more information on how this processed played out last time and use this as a guide as what to expect in the future. How rapid the post case zero changes were may help in an understanding of how quickly a vaccine based on case zero would become impotent. If we were lucky enough to find early pandemic or pre case zero sequences we might see how well adapted the virus was at the moment R0 became greater than one and so get a better feel for how close H5N1 is to reaching that point.