2015-12-13 10:16:21
I believe that a magnificent example to understand the difficulty of biomedical research and how much we still do not know about the molecular mechanisms of life is provided by viruses, particularly the most studied of them and not yet defeated: the immunodeficiency virus. human or HIV, which causes the disease AIDS.
The HIV virus has a genome of only 9,719 letters and produces only 15 proteins. Compared to the billions of letters in the genomes of complex animals or plants, and the tens of thousands of proteins that these organisms generate, we can say that the HIV virus is a fairly simple organism. However, this simplicity is only apparent. We do not yet know all the molecular mechanisms that the virus uses to evade the action of the immune system and to manipulate the cells it infects so that they dedicate themselves to making new viruses above other functions that they can perform.
And it is that in order to maximize its effectiveness, it seems increasingly clear today that the proteins that the HIV virus produces, from the point of view of their functions, are very similar to those multi-use Swiss knives, which just as well peel a potato that they tighten the screw that the neighbor usually has loose in his head. Thus, a single virus protein is also multi-purpose and can affect various cellular processes in ways that benefit the virus in its reproductive target.
Clearly, this property of virus proteins makes it more difficult for us to understand all the functions they perform. To further complicate matters, it is also known that cells have counterattack mechanisms that try to neutralize the actions of the virus proteins. Knowing what they are can be very important to enhance them and reduce their infective capacity.
To find out how important a particular protein is for the virus, researchers can now remove it from its genome, thanks to modern molecular biology techniques, and study whether or not the virus is capable of reproducing. Thus, it has been verified that one of the very important proteins for the reproduction of the HIV virus is the protein called Nef. Among its various functions, Nef appears to increase infectivity. HIV viruses without the Nef gene reproduce poorly, although sometimes the virus can reproduce without problems in certain cells.
warning sign
The reason for this difference was unknown, although it is reasonable to assume that cells in which HIV viruses lacking Nef reproduce without problems must lack the countermeasure against this protein. However, those cells in which Nef-deficient HIV viruses reproduce poorly must have this active mechanism.
To find out which cellular genes and proteins are involved in this mechanism of resistance to HIV, researchers at the University of Geneva in Switzerland delete the Nef gene from the HIV virus and infect various types of cells with it in the laboratory. As expected, some cells were much more resistant to the Nef-deficient virus than others.
The researchers then carried out an analysis of the genes that the cells had working, looking for any that worked much more intensely in the resistant cells than in those sensitive to HIV. Thanks to new statistical techniques for comparing gene function levels, which the researchers themselves are developing, they are able to identify a gene, called SERINC5, which produces high levels of protein. This protein is located in the outer membrane of cells, which it crosses from the inside out nine times.
Thus, the function of the protein produced by SERINC5 must be counteracted by Nef, which favors the infectivity and reproduction of the virus. When SERINC5 is absent or in low amounts, Nef is not required for the virus to infect cells.
What does this protein do to affect the infective capacity of the virus?
The researchers explain that the function of the protein develops in two stages. In the first, the virus infects cells without problems. When new viruses have been produced and they leave cells, they take part of the cell membrane with them to build their own protective membranes. In these membranes, viruses inevitably carry with them the SERINC5 protein of the first cell they infected.
Now, in a second stage, the viruses try to infect new cells, but in this case the SERINC5 protein acts as an alarm signal for these cells, and the virus is unable to infect them. Studies show that the virus’s Nef protein prevents SERINC5 from incorporating into the viral membrane and issuing this alarm signal, making it crucial for HIV viruses to continue to infect cells. However, the researchers also reveal that if the infected cell has a high amount of SERINC5, even Nef cannot prevent it from being incorporated into the viral membrane, which leads to the infection stopping.
These findings, published in the latest issue of Nature, suggest that if it were possible to stimulate the functioning of the SERINC5 gene in AIDS patients, along with the antiretroviral therapies that we already have, it might be possible to stop the reproduction of the gene altogether. virus and get to cure the disease. This, today, is just a hope, but if there are hopes in this world with foundation, those are the ones based on science.
Reference:
Annachiara Rosa et al. (2015). HIV-1 Nef promotes infection by excluding SERINC5 from virion incorporation. Nature.
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