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With the tamiflu resistance now becoming evident in swine flu, would it be better to keep relenza on hand rather than tamiflu? (in terms of which is more likely to remain effective around October)
A sequence not in the database (the swine database is not very robust).
I hope this isn't using up my daily question allowance, but since you brought up the high portion of the PB1.....
Does swine flu have a truncated or intact PB1-F2? I ask after reading the following at the reference cited:
Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 12, No. 10, October 2006 1607 Influenza A Virus PB1-F2 Gene
To the Editor: Recently, Chen and
co-workers described the expression
of an 11th influenza A virus protein,
designated PB1-F2 because this protein
is encoded in the +1 open reading
frame of the segment-2 RNA (1).
Later, Chen et al. presented a preliminary
analysis of 336 PB1 sequences
from GenBank (2). We have extended
the work on PB1-F2 and analyzed
1,864 partial and complete segment-2
sequences deposited in GenBank;
these sequences belong to 79 influenza
A virus subtypes. In summary, the
following 8 observations should
receive attention:
First, the size of PB1-F2 polypeptides
ranges from 79 to 101 amino
acids (aa); most isolates encode versions
of either 87 or 90 aa. Because
polypeptides of 79 aa are located
within mitochondria, their truncation
has no effect on the protein function.
The frequency of the 79-aa PB1-F2 is
≈5%.
Second, a functional PB1-F2 is
expressed by 92% of all segment-2
sequences, i.e., a polypeptide >78 aa.
The proportion of intact PB1-F2
varies according to host (humans
90%, swine 76%, other mammals
100%, birds 95%).
Third, the H1N1 subtype comprises
3 genetic lineages. One clade has 2
branches: 1 branch includes the
human viruses, with the pandemic
1918 virus at its root; the other branch
includes the classic swine viruses.
The third clade represents the
European porcine isolates. Although
all classic swine sequences have a
truncated PB1-F2 (in-frame stop
codons after 11, 24, and 35 codons),
the early human isolates (H1N1
sequences from 1918 through 1947)
have an intact PB1-F2. After 1956,
however, a mutation became prevalent
such that the recent sequences
starting from A/Beijing/1/56 terminate
after 57 codons. An exception to
this rule is A/Taiwan/3355/97. Two
human H1N1 isolates with an intact
PB1-F2 coding sequence cluster in
the H3N2 clade (A/Kiev/59/79,
A/Wisconsin/10/98). The PB1
sequences of European porcine
influenza A virus isolates cluster with
European porcine H3N2 and H1N2.
Fourth, all H2N2 sequences are
monophyletic and encode an intact
PB1-F2. Fifth, the main sequence
cluster of the H3N2 subtype comprises
3 branches: 1) porcine H3N2 and
porcine H1N2 sequences from the
United States, 2) porcine H3N2 isolates
from Hong Kong and human
H1N2, and 3) recent human H3N2
and some Japanese H3N2 isolates.
Most of these sequences encode an
intact PB1-F2.
Sixth, the cluster of European
porcine influenza A virus isolates
comprises the subtypes H1N1, H1N2,
and H3N2. The lack of distinct clades
for each subtype indicates frequent
reassortment in the evolution of these
viruses. Of the segment-2 sequences,
56% encode an intact PB1-F2.
Seventh, other porcine isolates of
various subtypes represent transspecies
infections or single reassortment
events. And eighth, the segment-
2 sequences of many avian
influenza A virus isolates encode
intact PB1-F2. Considerable proportions
of truncated PB1-F2 genes were
found in the H5N2, H6N6, H9N2,
and H13N2 subtypes. However,
because of the small number of
sequences available, this observation
may not be important.
In conclusion, PB1-F2 is
expressed in most avian and many
porcine influenza A virus isolates.
This finding contrasts with those in
the initial publication, which stated
that PB1-F2 is not expressed in many
animal isolates, particularly those of
porcine origin (1). Because PB1-F2 was described as a proapoptotic protein probably counteracting the host immune response, why numerous human and porcine isolates lack this protein without selective disadvantage remains unclear.
Roland Zell,* Andi Krumbholz,*
and Peter Wutzler*
*Friedrich Schiller University, Jena,
Germany
References
1. Chen W, Calvo PA, Malide D, Gibbs J,
Schubert U, Bacik I, et al. A novel influenza
A virus mitochondrial protein that
induces cell death. Nat Med.
2001;7:1306–12.
2. Chen GW, Yang CC, Tsao KC, Huang CG,
Lee LA, Yang WZ, et al. Influenza A virus
PB1-F2 gene in recent Taiwanese isolates.
Emerg Infect Dis. 2004;10:630–6.
Address for correspondence: Roland Zell,
Institute of Virology and Antiviral Therapy,
Medical Centre at the Friedrich Schiller
University, Hans Knoell Str 2, D-07745 Jena,
Germany; email: Roland.Zell@med.uni-jena.de
In response: Zell et al. (1) performed
an extensive genetic investigation
of PB1-F2, based on up-to-date
GenBank sequences. Their sample
size (1,864) greatly outnumbered ours
(336) in a previous study (2) and thus
definitely better portrays the genetic
characteristics of PB1-F2. We appreciate
their analyzing these samples by
subdividing nonhuman strains into
different species, which we did not do
(2). Their analysis is especially meaningful for the global pandemic threat from avian influenza viruses, which increases the need to study interspecies adaptation and transmission.
Zell et al. found that 92% of PB1
RNA encodes a functional PB1-F2,
compared with our 79% (264/334),
which supports the increasingly crucial
role of PB1-F2 in influenza virology.
They found the proportion of
intact human PB1-F2 to be 90%, a
substantial boost from our 68%
(67/99), which was based on data
from late 2003 (2). This increase is
apparently caused by the increasing
number of human H3N2 sequences
(mostly encoding an intact PB1-F2
compared with H1N1) deposited in
the past 2 years.
Human H1N1 from 1918 through 1947 contains full-length PB1-F2, whereas human H1N1 beginning in 1956 has a truncated PB1-F2 after codon 57. As reported by Zell et al., only 3 human H1N1 strains contain full-length PB1-F2: A/Kiev/59/79, A/Taiwan/3355/97, and A/Wisconsin/ 10/98. The PB1 genes of A/Kiev/
59/79 and A/Wisconson/10/98 were found clustered with human H3N2 as
a result of natural reassortment
between human H1N1 and H3N2
strains. On the other hand, the asynonymous
mutation found on
A/Taiwan/3355/97 enabled the translation
to get past the usual stop codon
at position 58, which other H1N1
strains exhibit. A/Taiwan/3355/97 (H1N1) was isolated from a patient with severe pneumonia. Animal study
has demonstrated that the existence of full-length PB1-F2 contributed to pathogenesis in mice (3). We speculate that the expression of a full-length PB1-F2 may contribute to disease severity in humans.
The C-terminal domain of PB1-F2
contains the mitochondrial signal and
can trigger apoptosis in specific
immune-related cells. Our recent
work (4) comparing avian and human
influenza A viruses also found that
many species-associated amino acid
signatures are located on the C terminal
of PB1-F2. This finding highlights the importance of further investigating the role of PB1-F2 on interspecies infection.
Guang-Wu Chen*
and Shin-Ru Shih*
*Chang Gung University, Taoyuan, Taiwan
References
1. Zell R, Krumbholz A, Wulzler P. Influenza
A virus PB1–F2 gene [letter].Emerg Infect
Dis. 2006;12:1607–8.
2. Chen GW, Yang CC, Tsao KC, Huang CG,
Lee LA, Yang WZ, et al. Influenza A virus
PB1–F2 gene in recent Taiwanese isolates.
Emerg Infect Dis. 2004;10:630–6.
3. Zamarin D, Ortigoza MB, Palese P.
Influenza A virus PB1–F2 protein contributes
to viral pathogenesis in mice. J
Virol. 2006;80:7976–83.
4. Chen GW, Chang SC, Mok CK, Lo YL,
Kung YN, Huang JH, et al. Genomic signatures
of human versus avian influenza A
viruses. Emerg Infect Dis 2006:9:1353–60.
Address for correspondence: Guang-Wu Chen,
Chang Gung University, Department of
Computer Science and Information
Engineering, 259 Wen-Hua 1st Rd, Kwei-shan ,
Taoyuan, Taiwan 333; email: gwchen@
mail.cgu.edu.tw
"The next major advancement in the health of American people will be determined by what the individual is willing to do for himself"-- John Knowles, Former President of the Rockefeller Foundation
With the tamiflu resistance now becoming evident in swine flu, would it be better to keep relenza on hand rather than tamiflu? (in terms of which is more likely to remain effective around October)
Both would be best (Relenza resistance may also be silently circulating and may appear as Relenza use increases).
"I hope this isn't using up my daily question allowance, but since you brought up the high portion of the PB1.....
Does swine flu have a truncated or intact PB1-F2? I ask after reading the following at the reference cited:"
AD: PB1 of Swine Flu has a stop condon (taa) that prevents the formation of the open frame 2 protein. Wouldn't take much of a change to allow formation, and the F2 characterics of Swine Flu appear to be problematic, closely matching prior pandemic viruses. Bears close monitoring.
.......Does swine flu have a truncated or intact PB1-F2? I ask after reading the following at the reference cited:"
AD: PB1 of Swine Flu has a stop condon (taa) that prevents the formation of the open frame 2 protein. Wouldn't take much of a change to allow formation, and the F2 characterics of Swine Flu appear to be problematic, closely matching prior pandemic viruses. Bears close monitoring.
thanks.
That issue looked like something to think about.
The more I read, the more I am amazed at how well this virus can perform its goal over many years by recycling strategies.
.
"The next major advancement in the health of American people will be determined by what the individual is willing to do for himself"-- John Knowles, Former President of the Rockefeller Foundation
I think it has 3 stop codons.
And even if they were replaced, it seems unlikely that the
rest could encode a useful protein.
And it would disturb the encoding of PB1
So it looks easier to me to get an entirely new segment 2
from some other virus
(classical swine)
or has human H1N1 PB1-F2, I forgot, but I assume not
I think it has 3 stop codons.
And even if they were replaced, it seems unlikely that the
rest could encode a useful protein.
And it would disturb the encoding of PB1
So it looks easier to me to get an entirely new segment 2
from some other virus
(classical swine)
or has human H1N1 PB1-F2, I forgot, but I assume not
BTW. what about N40
GS: the stop condon is "taa" at position 128-130 of PB1 (11 amino acids into the F2 protein). It is the only one of which I am aware, and should you have one nucleiod change to drop the stop condon, then F2 should be produced with some nasty looking markers that closely track other problem viruses.
And yes, both H1N1 and H3N2 seasonal flu viruses code for the F2 protein.
As to "N40", you will have to enlighten me as to what that is or means. I'm not sure I understand that last question.
I think it has 3 stop codons.
And even if they were replaced, it seems unlikely that the
rest could encode a useful protein.
And it would disturb the encoding of PB1
So it looks easier to me to get an entirely new segment 2
from some other virus
(classical swine)
or has human H1N1 PB1-F2, I forgot, but I assume not
BTW. what about N40
Please. Many flu genomes have no stops and have fully functional PB1 (which is the point).
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