Pandemic H1N1 evolution scenario:
Multiple non-competing variants?
As pandemic H1N1 fall wave evolves, questions arise on possible 1918 pandemic parallels. Differently from 1957 an 1968 pandemics, 1918 pandemic, has all 8 mRNA segments markedly different from recent seasonal influenza. The same is truth about the 2009 pandemic H1N1 genome.
Among possible parallels the 1918 pandemics singular timing
is the major source of concern.
The 1918 pandemic presented 3 sucessive waves over a 9 months period. Other pandemics show different interplays with influenza seasonality, spanning longer periods (2-5 years). It has been proposed that 1918 pandemic would require the presence of non-competitive virus variants to cope with that pattern.
We examine in this thread some potentialities of a similar scenario for the 2009 pandemic H1N1, conjecturing it could evolve toward a number of non competitive fit variants
sharing rather similar HA and NA, and therefore, roughly equivalent vis a vis
the human adaptive immune response. That is the reason why vaccines
use HA an NA segments only.
The crucial point is that they are non competing
variants. Of course a fit improvement would make the variant “more competitive
”, in the sense that it becomes potentially harmful. However, as far as our immunological system is concerned, genetic changes on other segments such as PB2 or NS would be barely distinguishable. This feature gives a “free pass” of the new variants, which can further reassort and/or recombine at will with the remaining pandemic H1N1 variants (under evolutionary pressure). Multiple variants can coalesce into a fewer number non competitive clades with different fits, which can potentially produce close spaced pandemic waves.
The same is not true with seasonal influenza
, since the host herd (their “habitat”, so to speak) already possess an acquired immune response
. Viruses don’t need to fight each other. The outspacing of competitive viruses is performed mainly by the host immunity to the old strain. It is an irony: our own immunologic fittnes paves the way to pandemic H1N1 introduction and hability to dominate the scene!
The concept of pandemic multiple fit variants was introduced by Taubenberger and Morens, as a crucial component of the epidemiologic scenario of “3 pandemic waves of 1918–1919, which occurred in the spring-summer, summer-fall, and winter (of the Northern Hemisphere), respectively”
As a guideline, an attached graphic allows comparison between the dynamics of 4 precedent influenza pandemics:
Pandemic_Waves_sKb_c.jpg [ 30.5 KiB | Viewed 1292 times ]
Mortality Distributions and Timing of Waves of Previous Influenza Pandemics.Time scales different to each graphic. Vertical stripes are winter influenza seasons. Vertical scales are also adapded to each pandemic. Mortality percentage on peak tops.
A number of H1N1 co-circulant variants scenarios
are reviewed below:HA
Co circulation of at least 2 H1N1 variants with slightly differents HA was conceived as a possible explanation of 1918 pandemics singular timing of 3 sucessive waves over a 9 months period (1).
A brief reminder of pandemic development:
“In the 1918–1919 pandemic, a first or spring wave began in March 1918 and spread unevenly through the United States, Europe, and possibly Asia over the next 6 months (Figure 1). Illness rates were high, but death rates in most locales were not appreciably above normal. A second or fall wave spread globally from September to November 1918 and was highly fatal. In many nations, a third wave occurred in early 1919.
Waves_1918_London.jpg [ 16.28 KiB | Viewed 909 times ]
The 1918 timing shows specific hallmarks and attempted explanations:“But 3 extensive pandemic waves of influenza within 1 year, occurring in rapid succession, with only the briefest of quiescent intervals between them, was unprecedented. The occurrence, and to some extent the severity, of recurrent annual outbreaks, are driven by viral antigenic drift, with an antigenic variant virus emerging to become dominant approximately every 2 to 3 years. … … The timing and spacing of influenza epidemics in interpandemic years have been subjects of speculation for decades. Factors believed to be responsible include partial herd immunity … … most favorable circumstances, which include lower environmental temperatures and human nasal temperatures … optimal humidity, increased crowding indoors, and imperfect ventilation due to closed windows and suboptimal airflow.
” “However, such factors cannot explain the 3 pandemic waves of 1918–1919, which occurred in the spring- summer, summer-fall, and winter (of the Northern Hemisphere), respectively. The first 2 waves occurred at a time of year normally unfavorable to influenza virus spread. The second wave caused simultaneous outbreaks in the Northern and Southern Hemispheres from September to November. Furthermore, the interwave periods were so brief as to be almost undetectable in some locales. Reconciling epidemiologically the steep drop in cases in the first and second waves with the sharp rises in cases of the second and third waves is difficult. Assuming even transient postinfection immunity, how could susceptible persons be too few to sustain transmission at 1 point, and yet enough to start a new explosive pandemic wave a few weeks later? Could the virus have mutated profoundly and almost simultaneously around the world, in the short periods between the successive waves? Acquiring viral drift sufficient to produce new influenza strains capable of escaping population immunity is believed to take years of global circulation, not weeks of local circulation. And having occurred, such mutated viruses normally take months to spread around the world.”.
A conceptual question is rised:"Were the 3 Waves in 1918–1919 Caused by the Same Virus? If So, How and Why?"
The multiple fits hypothesis is proposed as an explanation of this sucecessive waves pattern: “…. at least 2 H1N1 receptor-binding variants co-circulated in 1918: 1 with high-affinity binding to the human receptor and 1 with mixed-affinity binding to both avian and human receptors.”
The authors refer to a number of HA SNP
differences among the 5 available 1918 isolates sequences. As explained earlier by the autors, “The switch from this avian receptor configuration requires of the virus only 1 amino acid change (30), and the HAs of all 5 sequenced 1918 viruses have this change, which suggests that it could be a critical step in human host adaptation. A second change that greatly augments virus binding to the human receptor may also occur, but only 3 of 5 1918 HA sequences have it
Note: The subject is discussed on the thread “Is the virus peaking?
” Page 4:http://fluboard.rhizalabs.com/forum/viewtopic.php?f=5&t=1308&start=20
also discussed on: http://fluboard.rhizalabs.com/forum/viewtopic.php?f=26&t=1053PB2
Clearly the genetic optimization of Polimerase Basic PB2 carries the key genetic signatures to optimized viral fitness specific to the human host. The PB2 E627K acquisition modulates the replication temperature in human nose in a cold weather is a classical influenza pandemic acquisition. As a matter of fact, “In both the reassortment events that generated the 1957 and 1968 pandemic viruses, the PB2 gene segment was acquired from a human virus
Recent PB2 E627K
detections in Netherlands is disussed on topic “[i]E627K In The Netherlands
A “H1N1 PB2 E627K short review
”, is presented on the thread “Sequence Updates
” (Oct 06, 2009 8:34 pm Post). http://fluboard.rhizalabs.com/forum/viewtopic.php?f=26&t=1053NS
Another strong candidate to strongly modulate H1N1 fitness in the human host is the Non Structural NS gene. It encodes the NS1 protein, responsible for the crucial interferon antagonist function. As pointed out By Wendy Barclay, “It is possible that avian virus NS1 genes do not function in this role efficiently in the mammalian host, perhaps due to inherent differences in innate immunity between birds and mammals.”
In 2009 H1N1 Swine
Origin Influenza, H1N1, some degree of mammalian adaptation is already accomplished. H1N1 NS gene can be traced to North American Classical Swine lineages. Mammalian adaptation certainly occurred along decades on swine hosts. However, swine is not just any mammalian! Swine are somewat more robust than humans, as far as influenza is concerned. Evolution pressure being smaller, swine influenza can preserve some older “avian-like” genetic properties. Therefore, H1N1 NS gene is also expected to evolve toward human host interferon antagonist optimization. I will show on the next post a comparison between NS1 gene of 1918 1solate, Pandemic H1N1 and seasonal H1N1.
It is worth to make a short reminder of the interferon role in host innate immune system: “When a virus enters a cell (left), the infection is sensed and the cell responds by producing IFNs. These cytokines bind to specific receptors on the cell surface, causing the production of hundreds of proteins encoded by interferon-stimulated genes, or ISGs. These proteins have anti-viral activity, and can stop a viral infection
However, “The fact that viruses routinely and frequently cause disease shows that our defense mechanisms are imperfect. This is in large part due to the fact that nearly every viral genome encodes one or more countermeasures to modulate host defenses. Influenza virus is no exception. One of the viral proteins, called NS1, is particularly adept at impairing the synthesis of interferons (IFN) by cells
Therefore, I believe H1N1 NS gene should be actively monitored, since minute modification in this gene can strongly modulate pathogenic levels via interferon antagonist.
(1) 1918 Influenza: the Mother of All Pandemics
Jeffery K. Taubenberger and David M. Morens, Emerging Infectious Diseases
, Vol. 12
, No. 1, January 2006
(2) Characterization of the 1918 influenza virus polymerase genes
Jeffery K. Taubenberger, Ann H. Reid, Raina M. Lourens, Ruixue Wang, Guozhong Jin & Thomas G. FanningNature
- Vol 437, 6 October 2005.
(3) Influenza virus : cell interactions
Wendy BarclayEmergence of New Epidemic Viruses through Host Switching
September 6-8, 2005
(4) Viral evasion of innate host defenses
Vincent Racaniello Ph.D.* - Virology blog
, 12 June 2009http://www.virology.ws/2009/06/12/viral-evasion-innate-host-defenses/* Professor of Microbiology at Columbia University Medical Center
(5)How influenza virus inhibits early antiviral responses
Vincent Racaniello Ph.D. Virology blog
, 4 June 2009http://www.virology.ws/2009/06/04/how-influenza-virus-inhibits-early-antiviral-responses/
(4) The NS1 Protein of the 1918 Pandemic Influenza Virus Blocks Host Interferon and Lipid Metabolism Pathways.
by: Rosalind Billharz, Hui Zeng, Sean C. Proll, Marcus J. Korth, Sharon Lederer, Randy Albrecht, Alan G. Goodman, Elizabeth Rosenzweig, Terrence M. Tumpey, Adolfo García-Sastre, Michael G. KatzeJournal of virology
(12 August 2009)