The "HIV" and influenza A virus genomes 26 July 2003
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Eleni Papadopulos-Eleopulos,
Department of Medical Physics, Royal Perth Hospital, Western Australia,
Valendar F Turner, John Papadimitriou, Barry Page, David Causer, Helman Alfonso

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Re: The "HIV" and influenza A virus genomes

The “HIV” and influenza A virus genomes

In his rapid response “Re: “HIV” genome, clones and sequences”, Christopher Noble wrote: “No references were provided…”.   In fact, a reference was provided, that is, reference 9 from which the quote concerning H1N1 influenza A virus was taken.

Christopher Noble wrote: “I am extremely interested to know why Papadopulos-Eleopulos is presenting what is clearly an exception as if it were the rule.”

The H1N1 influenza A virus is not an exception.   The quote concerning H1N1 influenza A virus from reference 9 is preceded by:

“Several sequencing studies have demonstrated extreme heterogeneity of viral populations.  Fiers and coworkers observed sequence heterogeneity when phage Qβ and MS2 were first sequenced.   Variability in several virus populations has been suggested by sequence differences among over-lapping cDNA clones generated from viral RNA.  Catteneo et al reported over 1% sequence difference among overlapping cDNA clones of measles virus RNA.

In spite of great heterogeneity within virus populations, high mutation rates are not always reflected in rapid evolution.  There are conditions under which viruses can replicate efficiently and continuously, and yet accumulate few if any viable, competitive mutations in the virus population.  The studies of Domingo et al with phage Qb first illustrated this.  The same wild-type sequence predominated through extensive passage despite the fact that a large portion of the population was shown to be variant at any one time.  Once a stable equilibrium population has been reached, virus may be able to replicate for extensive period with little evolution as long as conditions remain unchanged.  This does not mean that the predominating sequence cannot stray to some degree from the master sequence or that a rare event (many mutations at one time, or a recombinational event) could not give rise to a more fit variant (a jump from one fitness peak to another).  It simply means that among the distribution of variants generated by the wild-type sequence, none have a competitive advantage over the parental master sequence.

Observations with VSV support this conclusion.  Laboratory strains of VSV with different passage histories over many years accumulated few if any nucleotide changes as revealed by T1 fingerprinting.  Spindler et al fingerprinted isolates obtained during 232 dilute passages of VSV in BHK21 cells.  Although several spot changes were seen in intermediate passages, all reverted to wild type by passage 232.  Recently, after 529 dilute passages of this virus, T1 oligonucleotide mapping again revealed the accumulation of not a single oligonucleotide spot change.

Other viruses also demonstrate remarkable stability in some situations.  The type 3 Sabin poliovirus vaccine differed from its neurovirulent progenitor at only 10 nucleotide positions after 53 in vitro and 21 in vivo passages in monkey tissue.”

The quote concerning H1N1 influenza A virus from reference 9 is then followed by:

“Rotavirus genome exhibited only limited heterogeneity after years of continuous passage.  Many selective forces may stabilise virus populations.  These stabilising factors may include the need for conservation of protein structure and function, RNA secondary structure, glycosylation sites, and phosphorylation sites.”

In conclusion :

(i)                 the evolution rate of H1N1 may be an exception in comparison with other influenza A viruses which are still very low (“0.2%”).   However, its evolution rate is not an exception regarding RNA viruses in general.

(ii)               Our interest is not in the evolution rates as such, but the genomic differences at a given time.   In this regard, the differences in the RNA viruses genomes are significantly less than in the “HIV” genome.

In Christopher Noble’s reference 1 where the “rapid evolution rate of approximately 2x10-3 substitutions per nucleotide site per year (0.2%)” of influenza A virus is discussed, the authors wrote: “…the length of time that a vaccine is effective against a viral pathogen may be correlated with the evolutionary rate of the virus.   Vaccines for all three poliovirus types are made with isolates obtained approximately five decades ago.   Similarly, the yellow fever virus vaccine was developed more than 50 years ago and current isolates have not sufficiently changed to warrant a new vaccine formula.   Also, the currently used rabies vaccine strain goes back to Pasteur’s time, whereas the influenza A viruses used for vaccine manufacture are changed every 2 to 3 years…”

Would please Christopher Noble tell us three things:

(i)                 Since an annual evolution rate of approximately 0.2% in the influenza A virus necessitates vaccine changes every two to three years, how is it possible to have an “HIV” vaccine when there are differences of up to 40% at any given time in the “HIV” genome? (Note that millions upon millions of dollars are being spent looking for such a vaccine) 

(ii)               How can such variation be compatible with the induction of the same biological effects and expression of antibodies which are detectable in a universally applied test?

(iii)             How is it possible for differences of up to 40% in the “HIV” sequences to represent the genome of one and the same object?

Competing interests:   None declared