HIV and AIDS: new data

Margarita Paimakova, Vesti 

Researchers from the Gladstone Institute found that HIV does not cause AIDS directly, by exposing the multiplied viral particles to the cells of the human immune system (HIV Particles Do Not Cause AIDS, Our Own Immune Cells Do).

HIV is able to infect an immune cell, that is, a cell of the body's defense system, and not cells of other tissues. That's why it's called that. The infected cell then transmits the virus to the uninfected. Cellular infection is 100-1000 times more effective, and a new study shows that a method that causes this kind of chain reaction forces cells, in fact, to commit suicide.

"The killers of CD4 T cells in lymphoid tissues are the infected cells themselves, and not the free–floating virus itself," says the lead author of the study, PhD student Gilad Doitsh, a researcher at the Gladstone Institute of Virology and Immunology. "Cell–to-cell transmission of HIV triggers a deadly disease process."

In a previous study, scientists found that 95% of cell deaths from HIV are caused by immune cells committing suicide in self-defense after an unsuccessful infection (to prevent the virus from copying itself and multiplying). When a virus invades a cell, it detects it and is deactivated, the spread of infection is interrupted. Nevertheless, fragments of viral DNA remain in this place and are found by the successors of the dead cell. They rush to the place of infection, pick up dangerous fragments and the process repeats, leading to the destruction of the "run-in" rescuers. That is, fragments of viral DNA cause a domino effect in the body's defense system: the enzyme caspase-1 is activated, which ultimately leads to pyroptosis – mass suicide of cells.

Now, researchers have come to the conclusion that this mass death is activated only by the transmission of HIV infection from cell to cell, and not due to infection of cells with free-floating viral particles.

Studying the lymphoid tissue affected by HIV, scientists compared the indicators of cell death from the transmission of the virus from cell to cell with cell death from a directly freely circulating virus. They found that while the overall infection rate remained the same, significantly more CD4 T lymphocytes died if HIV was spread by cell-to-cell transmission than from a free-floating virus.

"Despite the fact that free-floating viruses give rise to infection, it is the subsequent spread of HIV from cell to cell that causes the mass death of CD4 T cells," explains co–author Nicole Galloway. "Such a method of HIV transmission is absolutely necessary to activate the pathogenic deadly process of HIV infection."

To confirm this conclusion, the researchers studied the transmission of the virus using a variety of techniques: a genetically modified virus, blocking the work of intercellular synapses, as well as increasing the physical distance between cells so that they could not contact each other. It is noteworthy that the violation of cell contact with each other stopped the death of CD4 lymphocytes. Moreover, only during the transmission of the virus from cell to cell, caspase-1 was activated in target cells, thereby initiating pyroptosis.

Scientists suggest that the difference in the "lethality" of the two methods of infection is associated with greater efficiency of transmission of the virus from cell to cell. Virus DNA fragments are quickly destroyed by immune cells after infection by the virus particles themselves, as a result, they are not detected by the defense systems of T-lymphocytes and do not lead to the self-destruction of the immune cell. However, during transmission from cell to cell, viral DNA fragments gradually accumulate in the cell until they exceed the threshold value and are not detected by protective systems. As a result, the process of self-destruction is initiated, and after it begins the mass death of CD4 T-lymphocytes.

Diagram from an article in Cell Reports – VM

Scientists believe that by learning how to stop the transmission of the virus from cell to cell, they will be able to block the deadly march of the virus through the body and slow down the progression of infection.

The work of Deutsch and his colleagues Cell-to-Cell Transmission of HIV-1 Is Required to Trigger Pyropotic Death of Lymphoid-Tissue-Derived CD4 T Cells is published in the open access edition of Cell Reports.

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31.08.2015