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ETH - Eidgenoessische Technische Hochschule Zuerich - Swiss Federal Institute of Technology Zurich
Section: Science Life
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Published: 11.03.2004, 06:00
Modified: 11.03.2004, 13:25
The importance of the recombination of HI-viruses
Often "wrongly" recombined

The immune deficiency syndrome, AIDS is a huge health problem worldwide – and will remain so for some time to come. One reason lies in the HI-viruses' ability to become resistant to specific drugs. Until now, scientists have supposed that the recombination of different viruses plays an important role here. But researchers at ETH now show that the recombination can in fact slow down the build-up of resistance and that it advances it under certain specific conditions. This throws light on the question of why sexuality exists.

By Christoph Meier

AIDS is still a health problem of gigantic dimensions. At the end of 2003 the World Health Organisation estimated that around 40 million people around the world were carrying the HI-virus. Drugs therapies to treat AIDS, heralded at the World's AIDS Congress in 1996 in Vancouver as a revolution, have been tempered by developments. This is not solely due to the fact that in regions where medication is available a certain lackadaisical attitude to AIDS protection has developed or because the virus continues to spread rapidly in other regions. One other important reason is the ability of the viruses to become resistant to medication.

Questions of resistance and recombination

So how do such resistances develop, especially to more than one type of drug? Apart from new mutations the combination of the HIV genome also plays a role. This process, known as recombination, is possible for AIDS viruses that carry two copies of their RNA genome in their membranes. If such a virus copies its genetic information after attacking a cell it often changes from one template to the other. If two different versions are now available – which can happen when a cell is attacked by more than one virus, leading to a "super-infection" – two different characteristics can be combined on one genome.

Even though it is quite easy to verify how multiple resistance develops in an HIV genome, there are no data or estimates on the effect of this process. Nevertheless, many scientists speculate that recombination must be a deciding factor. This state of affairs was a thorn in the side of Sebastian Bonhoeffer, ETH professor of theoretical biology (1). Because, in principle, recombination can lead to unfavourable combinations as well to favourable ones. Together with his team Bonhoeffer developed a mathematical model which integrated recombination. In a recently published paper (2), he has now been able to show that the influence of recombination has been overestimated, and what's more, that under certain conditions, this rearrangement of the genome even slows down the ability of the virus to build up resistance.

A question of the epistasis

For their study the researchers started with genes that possessed two variants. In each case, one was resistant to a specific drug and the other was a "wild type". The latter, in the absence of medication, was attested a higher degree of fitness. With drug therapy, the opposite was the case. Data used for the model included selection, mutation, superinfection and the interdependency of two genes on one genome. This interdependency was allowed to be positive, neutral or negative, and assigned to a synergistic, non-existent or antagonistic epistasis, respectively. So a synergistic epistasis means that a second mutation on the genome leads to a greater loss of fitness than expected.


Investigating the consequences of recombination in HI viruses: Christian Althaus (right) and Sebastian Bonhoeffer. large

When the model was run, the research team saw that the effect of recombination on the appearance of viruses with multiple resistance decisively depended on the type of epistasis. Only in synergetic epistasis do recombinations facilitate the evolution of resistances. An antagonistic epistasis slows the process down. The influence of recombination was generally quite weak, regardless of its frequency. In the model a superinfection without treatment increases the number of double resistant viruses; under the pressure of medication, the situation changed to the reverse. This result reflects a peculiarity of the virus. If two viruses with different degrees of fitness meet in a cell by superinfection, the membrane of any new virus to develop will be a combination of both variants, regardless of whether only the genome of the fittest is packed in. The genome of the fitter virus therefore suffers under the protein dowry of the lesser-fit virus.

Treatment and "why sex?"

So what are the possible consequences of this model for the ETH research team? Sebastian Bonhoeffer points to two aspects, the first of which is medical. If gene variants that are antagonistic to one another exist, then the build-up of resistance to a combination of drugs that favours such genes would be slowed down by recombination. What is missing from the picture is information on how strongly certain mutations in the HIV genome act synergistically or antagonistically on one another. Bonhoeffer now wants to turn his attention to this question using HI-virus data sequences, which he has in abundance.

However, such an analysis is not only relevant from a medical point of view. Bonhoeffer comes to his second point. It is highly possible that the results of such an investigation could also deliver insights into a far more fundamental question; why on earth does recombination exist? Because, as Bonhoeffer's model shows, in many cases this process has unfavourable consequences for HI-viruses. From an evolutionary point of view, it must be presumed that, under certain circumstances, the acquisition of recombination is advantageous. If these circumstances can be identified in the case of the HI-viruses then conclusions might be drawn on the reason – or reasons – for recombination in higher-order beings. Even though sexual reproduction and concomitant recombination is widespread, the advantages of sex as a means of reproduction is still one of biology's better kept secrets – despite numerous theories.

Cf. ETH Life report on Bonhoeffer's research on HI viruses "Mathematics against AIDS":

(1) Research project of the theoretical biology team:
(2) “Recombination in HIV and the evolution of drug resistance: for better or for worse?”, Bretscher MT, Althaus CL, Muller V, Bonhoeffer S, BIOESSAYS 26 (2): 180-188 FEB 2004

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