Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

HIV: a sugar shield to evade host defences

30.04.2004


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.

Bénédicte Robert | EurekAlert!
Further information:
http://www.ird.fr/us/actualites/fiches/2004/198.htm

More articles from Health and Medicine:

nachricht Millions through license revenues
27.04.2017 | Rheinische Friedrich-Wilhelms-Universität Bonn

nachricht New High-Performance Center Translational Medical Engineering
26.04.2017 | Fraunhofer ITEM

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Making lightweight construction suitable for series production

More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.

Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...

Im Focus: Wonder material? Novel nanotube structure strengthens thin films for flexible electronics

Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.

"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...

Im Focus: Deep inside Galaxy M87

The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.

Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...

Im Focus: A Quantum Low Pass for Photons

Physicists in Garching observe novel quantum effect that limits the number of emitted photons.

The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...

Im Focus: Microprocessors based on a layer of just three atoms

Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.

Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Fighting drug resistant tuberculosis – InfectoGnostics meets MYCO-NET² partners in Peru

28.04.2017 | Event News

Expert meeting “Health Business Connect” will connect international medical technology companies

20.04.2017 | Event News

Wenn der Computer das Gehirn austrickst

18.04.2017 | Event News

 
Latest News

Wireless power can drive tiny electronic devices in the GI tract

28.04.2017 | Medical Engineering

Ice cave in Transylvania yields window into region's past

28.04.2017 | Earth Sciences

Nose2Brain – Better Therapy for Multiple Sclerosis

28.04.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>