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14 jaanuar 2019, 14:38

One of the HIV proteins is able to slow down the movement of infected T-cells and increase the survival rate of the virus

One of the HIV proteins is able to slow down the movement of infected T-cells and increase the survival rate of the virus - pilt 1

A group of scientists from the Massachusetts General Hospital (MGH) conducted a study that revealed the specific function of the Nef protein, which is part of the HIV structure, which, according to them, slows the spread of the virus in the very early stages of the infection, but helps it to survive further by avoiding the immune answer. The results of the work were published in Cell Host & Microbe.

“HIV uses several proteins with a number of functions that, according to current ideas, determine the patterns of movement of infected cells,” says team leader Dr. Torsten Mempel from the Center for Immunology and Inflammatory Diseases MGH.

“Our study revealed a special function of the Nef protein, which is responsible for impaired ability of infected T cells to move [...] [This function is aimed at] slowing down the rate at which the virus initially spreads after infection. However, this same function allows the virus to persist at later stages when the adaptive immune response is activated - especially the response of cytotoxic "killer" T cells [...] These results show that this Nef function has evolved to help HIV avoid an immune response due to a slower original distribution [...]. ”

Recent studies by Dr. Mempel’s group have shown that, unlike the generally accepted idea of ​​the spread of HIV throughout the body as free virus particles, it is spread throughout the body by infected T-cells that pass through tissues and the circulatory system and enter in direct contact with uninfected cells. Since it was previously shown that Nef inhibits the function of several proteins involved in signal transmission, and disrupts the processes that are thought to control cell migration, the MGH team examined in detail how Nef and other HIV proteins have an effect on the movement of infected T- cells.

Their experiments on mice with key elements of the human immune system — an animal model capable of becoming infected with HIV — confirm previous findings that Nef reduces the rate of migration of infected cells by disrupting the assembly and disassembly of a protein called actin.

Actin filaments support the shape of the cells and allow them to move, pushing the outer membrane on one side, simultaneously pulling the membrane on the other. This function of Nef is accomplished through the interaction of a “hydrophobic spot” —a group of water-repellent amino acids located on the surface of the protein — with a group of cellular proteins, including an enzyme called PAK2.

In the first weeks after the mice were infected with two strains of HIV, one with the mutant form Nef (Nef-M), which had a “hydrophobic spot” disturbed, and one non-mutant strain, Nef-M became dominant: infected T cells with it spread faster.

However, over time, Nef-M disappeared, and the HIV strain without mutation became dominant, which coincided with an increased activity of the cytotoxic T-cell response against HIV.

The authors also found that in cell studies there was no visible benefit for the virus from the “hydrophobic spot” of the “non-mutant” Nef. This, experts say, suggests that this advantage has developed in response to the pressure of the animal's immune system.

“We know that other functions of Nef seem to have evolved to help HIV avoid an immune response, so it can be assumed that disruption of the actin cytoskeleton serves the same purpose,” noted Dr. Mempel.

“The fact that it manifests itself only in living models clearly indicates that the important biological properties of the virus are not evident in the cell culture systems traditionally used to study HIV. This means that much remains to be learned about what HIV can do and what its potential weaknesses are. ”

"It is important that if it becomes possible to direct the ability of Nef to disrupt the cytoskeleton, we can increase the vulnerability of HIV to antiviral treatment strategies, such as vaccination or widely neutralizing antibodies."

Autor: Olga Moiseeva

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