The evolution of RNA viruses. 4 November 2003
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Brian T Foley,
HIV Researcher
Los Alamos National Lab, Los Alamos, NM 87545 USA

Send response to journal:
Re: The evolution of RNA viruses.

In discussing the variability observed in HIV-1 M and O group genomes compared to the variability in the genomes of other RNA viruses, the Perth group wrote:

"...
Let us again reiterate that the 1% variability is not our claim but that of a number of virologists.
..."

Can you please give us the name of two or three of these virologists who claim that RNA viruses don't differ by more than 1%?

On April 25th the Perth Group wrote:
"...
there is no proof for the existence of a unique molecular entity, "HIV-RNA" or "HIV-DNA", while the genomes of the most variable RNA viruses do not differ by more than 1%. The difference between the human and the chimpanzee genomes is no more than 2% while there is up to 40% variation between "HIV" genomes;
..."

On July 18th the Perth Group wrote:
"...
The difference between the sequences of the chimpanzee genome and the human genome is less than 2%, while the genomes of RNA viruses do not differ by more than 1% and even this 1% sequence differences are considered to represent "extreme variability". (9)
(9) Steinhauer DA, Holland JJ.
Rapid evolution of RNA viruses.
(1987) Annual Review of Microbiology 41:409-433.
..."

On 21 August the Perth Group wrote:
"...
The reference in which we said it is stated that even a 1% difference is considered to represent “extreme heterogeneity of viral populations” (8) was given before in our rapid responses “”HIV” genome, clones and sequences” (18 July 2003) and “The “HIV” and influenza A virus genomes” (26 July 2003).
8. Steinhauer DA, Holland JJ.
Rapid evolution of RNA viruses.
(1987) Annual Review of Microbiology 41:409-433.
..."

It has been repeatedly pointed out to the Perth group, for example on Sept 5th by Chris Noble:
"... Continuing to cite the review by Steinhauer (2) and claiming that it says that "the genomes of the most variable RNA viruses do not differ by more than 1%" will not help. It does not state this anywhere in the review.

The figure of 1% refers to a study by Cattaneo et al. It refers to the intrahost variation of the M protein coding sequence of the Measles Virus in the brain tissue of patients suffering from SSPE.
..."

that all RNA viruses are highly variable, and that the lentiviruses are not exceptional in their variability. Yet the Perth group continues to claim that there are virologists who claim that RNA viruses do not differ by more than 1%.

On Sept 22 the Perth Group wrote:
"...
In the review paper “Rapid Evolution of RNA Viruses” where about 1% variation is considered to be “extreme heterogeneity”, the authors wrote: “the relative growth rate of a variant must be extremely close to that of the wild type (within 0.01-0.1%) in order to be detected by ordinary sequencing of the equilibrium population…Many selective forces may stabilize virus populations. These stabilizing factors may include the need for conservation of protein structure and function, RNA secondary structure, glycosylation sites and phosphorylation sites.” (3)
(3) Steinhauer DA, Holland JJ. (1987).
Rapid evolution of RNA viruses.
Annual Review of Microbiology 41:409-33.
..."

Steinhauer and Holland, are discussing "stabilizing forces" or negative selection, which is selection pressure on an organism to remain the same over time. The opposite forces are called positive selection, such as selection pressure by the host immune system to eliminate viruses that remain unchanged and allow mutant viruses to become dominant in the population. Both forces are operating on all viruses that are exposed to host immune systems, however a virus like the human influenza virus jumps from one host individual to the next before the first host individual has mounted much immune response. Retroviruses on the other hand remain in an infected host for life, and must evade the host immune response over a longer period of time.

A huge amount of work has been done in characterizing the evolution of lentiviruses both within a single host individual and over great distances of time (1-6). The results prove beyond any reasonable doubt that HIV-1, HIV-2, SIV-AGM, SIV-CPZ, SIV-SMM, FIV-Puma, FIV-housecat, EIAV and other lentiviruses are exogenous, rapidly multiplying retroviruses which face relatively strong selection pressures from their host's immune system. The env gene of HIV-1 is observed to evolve at roughly twice the rate of the gag gene of HIV-1, because the env gene is selected by both antibody (humoral response) and CTL (cellular response) host immune responses, while the gag gene is selected primarily by only CTL responses.

Viruses in freezers, or grown in cell culture, do not face the same immune selection pressures, which is why it was possible to determine that the H1N1 influenza virus which made a reappearance in humans in 1977 had been "dormant" and not circulating in man, bird or other animal during its 27 years of absence from the human influenza pandemic (7).

Endogenous retroviruses also do not evolve rapidly over time. The endogenous retroviruses found in chimpanzees and humans are nearly identical, despite the several millions of years of time seperating us from our most recent common ancestor.

1: Yang W, Bielawski JP, Yang Z.
Widespread adaptive evolution in the human
immunodeficiency virus type 1 genome.
J Mol Evol. 2003 Aug;57(2):212-21.
PMID: 14562964

2: Rodrigo AG, Mullins JI.
Human immunodeficiency virus type 1 molecular evolution
and the measure of selection.
AIDS Res Hum Retroviruses. 1996 Dec 10;12(18):1681-5.
PMID: 8959243

3: Ross HA, Rodrigo AG.
Immune-mediated positive selection drives human
immunodeficiency virus type 1 molecular variation
and predicts disease duration.
J Virol. 2002 Nov;76(22):11715-20.
PMID: 12388731

4: Halapi E, Leitner T, Jansson M, Scarlatti G, Orlandi P,
Plebani A, Romiti L, Albert J, Wigzell H, Rossi P.
Correlation between HIV sequence evolution, specific
immune response and clinical outcome in vertically
infected infants.
AIDS. 1997 Nov 15;11(14):1709-17.
PMID: 9386805

5: Howe L, Leroux C, Issel CJ, Montelaro RC.
Equine infectious anemia virus envelope evolution in vivo
during persistent infection progressively increases
resistance to in vitro serum antibody neutralization
as a dominant phenotype.
J Virol. 2002 Nov;76(21):10588-97.
PMID: 12368301

6: Barouch DH, Kunstman J, Glowczwskie J, Kunstman KJ,
Egan MA, Peyerl FW, Santra S, Kuroda MJ, Schmitz JE,
Beaudry K, Krivulka GR, Lifton MA, Gorgone DA,
Wolinsky SM, Letvin NL.
Viral escape from dominant simian immunodeficiency virus
epitope-specific cytotoxic T lymphocytes in DNA-vaccinated
rhesus monkeys.
J Virol. 2003 Jul;77(13):7367-75.
PMID: 12805435

7: Laver WG, Webster RG, Chu CM.
From the National Institutes of Health. Summary of a
meeting on the origin of pandemic influenza viruses.
J Infect Dis. 1984 Jan;149(1):108-15.
PMID: 6198405

Competing interests: None declared