The extreme diversity of human immunodeficiency virus (HIV) strains is a major obstacle to anti-AIDS vaccine elaboration or the development of new treatments against the disease. IRD scientists, working jointly with other institutes (1), used statistical methods to determine the adaptive molecular mechanisms the virus deploys to avoid neutralization by the host immune defences. This adaptive molecular evolutionary strategy, based on genetic variability, proved to be a feature common to the different HIV subtypes. The virus apparently uses the great variety of its envelope-protein receptor binding sites, which have the role of fixing large complex carbohydrate molecules in the form of glycans, to provide protection against the host's antibodies. These sugars are large structures that apparently block the way of human antibodies that would otherwise fix on to the virus, without hindering these envelope proteins in their function of attaching the virus to the host cell. These results open the way to potential ways of tackling AIDS.
In humans, the AIDS virus HIV manifests extreme genetic variability. It is particularly virulent, probably because its introduction into populations is recent (2). It has a potential for rapid evolution, at both population and individual scales, owing to a mutation rate among the highest in the living world, and to its recombination capacity. This high evolutionary potential is one of the major obstacles hindering the development of an effective vaccine. Starting from the principle that this mutation-based evolution of the virus is a response to selective pressures exerted by the host immune response (thought to be the dominant evolutionary force) , IRD researchers and their project partners (1) attempted to determine, at the molecular scale, the adaptive mechanisms at work and their comparative occurrence between the different HIV groups and subtypes. They used powerful statistical techniques (the codon-based maximum likelihood method) to investigate and compare the evolution of 3 major genes of the HIV genome, gag, pol and env. They did this for several HIV subtypes. They were able to confirm that the virus followed a dynamic adaptation strategy, based on the deployment of a shield of complex carbohydrates (glycans) to block antibody binding and thus provide protection against the host immune response.
Among the mutations randomly affecting the genome as a whole, those which influence the genes essential for viral survival and multiplication appear to be systematically selected against (negative selection). The gag gene, which codes for the proteins of the capsid (containing the genome and the viral proteins) and the pol gene, which allows synthesis of enzymes essential for virus replication, thus appear highly conserved and stable from one subtype to another.
However, the env gene, which codes for the virus's envelope proteins, targets of the host's immune system antibodies, appears to contain positively selected sites: at the point on the genome where this gene is located, the mutations would be maintained as carriers of evolutionary advantage. They would allow diversification of the proteins expressed which, in this way, would no longer be recognized by the antibodies. However, these same proteins must conserve their vital function of binding the viral particle to the host-cell membrane (the CD4 of the immune system), which implies that on the env gene, the virus would manage to reconcile two opposing selection forces, one diversifying, the other conservative.
The research team used statistical significance tests to identify this positive selection at the scale of the protein expressed by the env gene, determine precisely the sites where it operates in the amino-acid sequence and compare the distribution of these sites in the 6 HIV subtypes studied. The results obtained showed that the mutations selected are not distributed randomly, but on given amino acid sites and in an identical way in the 6 HIV subtypes. These variants could all therefore be subject to the same selection pressure exerted by the immune system which, conversely, would react in the same way to each of these subtypes. Moreover, these positive selection sites appeared not be correlated with the virus recognition sites by the antibodies (epitopes), but with the glycosylation sites on the protein surface to which the sugars are bound. In this way a recent hypothetical model (3) envisaging the use by the virus of extremely large complex sugars to evade the host's immune system. These sugars fix on to the glycosylation sites, creating a spatial mask, and prevent the antibodies from binding to the virus recognition sites.
Selection pressure by the immune system acts on these sites. They appear to change their spatial configuration and thereby the position of the sugar molecules. Thanks to this modifiable sugar shield, the virus evades the antibodies without harming its ability to fix on to host cells. This investigation confirmed the theoretical model involving a common viral strategy for the whole range of HIV subtypes tested. It therefore provided information of vital importance for the development of new treatments and, possibly, of a candidate vaccine against Aids, viable for all HIV strains. Other research work is planned aiming to reinforce these results and further the studies on the variability in the primates of the SIVs, which originated the ancestors of human HIVs.
Source: Eurekalert & othersLast reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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