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16/04/2004 - Researchers in France have discovered how HIV hides itself from the host immune system, raising the possibility of developing new drugs or vaccines for the disease, reports Phil Taylor.
Because HIV mutates so rapidly, the body is unable to mount an effective immune response to the infection, and this is one of the reasons why the virus is so virulent. This genetic variability also makes it extremely hard to design a vaccine that can protect against the virus, and to date no effective vaccine has been developed for HIV.
Now, scientists at the Institut de Recherche pour le Developpement in Paris have determined that HIV hides by creating a shield of sugar-like molecules(glycans) to block antibody binding and thus provide protection against the host immune response. The finding could lead to new drugs that block the formation of this shield, exposing the virus to the host immune response, or even a single vaccine that could tackle all strains of HIV.
It is thought that the most powerful driver for HIV's adaptation in the body is the host immune response, which selects for those virus strains that successfully evade detection. To analyse the mechanisms at work across the different HIV groups and subtypes, the researchers compared the evolution of three major genes of the HIV genome: gag, pol and env.
They found that 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 - the 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.
The researchers postulated that this would allow diversification of the proteins expressed which, in this way, would no longer be recognised by the antibodies.
However, these same proteins must conserve their vital function of binding the viral particle to the host-cell membrane (the CD4 cell of the immune system). This suggests that to be beneficial any evolutionary pressure on the env gene, would also have to retain HIV's CD4-binding ability.
The research team used statistical tests to identify this positive selection at the scale of the protein expressed by the env gene, determine 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 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. This ties in with the theory that the virus uses extremely large complex sugars to evade the host's immune system, according to the IRD researchers.
The finding will be of interest to companies developing antiretroviral regimens, which are based on cocktails of drugs, usually with different modes of action, to reduce the chances that the virus will develop resistance to therapy.
For years, the only available treatments have been reverse transcriptase inhibitors and HIV protease inhibitors, but last year these were joined by a new class, the fusion inhibitors, in the form of Roche and Trimeris' Fuzeon (enfuvirtide). Meanwhile, there are six million HIV sufferers in developing countries, and only around 400,000 of these have access to antiretroviral drugs, which pose a major cost burden to healthcare systems as they must be dosed for life. So the prospect of a broadly-effective vaccine - that could be used in both the developed and developing world - is the most tantalising element of the new research.
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