The flaws of HIV

To defend themselves against viral infections, our cells use a variety of biological weapons. But viruses mutate faster than the eukaryotic cells we are made of, reason why they have so-called "countermeasure" proteins that allow them to divert the effectiveness of our immune system. The Nef protein appears to be one of them and, it is known to play a fundamental role in its replication and the development of AIDS. Multifunctional, Nef is particularly capable of altering the activation state of T lymphocytes and macrophages, cells essential to our immune mechanism. However, these regulatory functions do not explain another role of Nef: its ability to enhance the infectivity of viral particles.

"When the virus replicates in a cell, it utilizes Nef in order to neutralize a specific protein whose function is to protect this cell against HIV. Our goal was therefore to identify this unknown protein to understand why some cells are more susceptible to HIV than others," explains Federico Santoni, co-author of the study, bioinformatician and computational biologist within Prof. Stylianos Antonarakis' research group at the Faculty of Medicine of the University of Geneva (UNIGE).

Finding the protein that defends our cells

The researchers examined cell lines coming from different organs in order to identify those that were most and least likely to be infected with HIV. To do so, they removed Nef from the virus -- the manipulated virus is called HIV?Nef -- to determine which microbiological elements, usually inhibited by Nef, could explain this greater or lesser sensitivity to infection. Thanks to large-scale bio-statistical calculation techniques developed at UNIGE, the scientists were able to measure, in each cell line, the levels of correlation between its receptivity to HIV?Nef and the amount of protein transcription (in other words the level of expression of tens of proteins present on the cell surface), in order to identify those which would enable cells to effectively fight against HIV. The scientists found that in the cell lines the least sensitive to HIV?Nef, a membrane protein, called SERINC5, was highly expressed, while it was not -- or almost not -- expressed in cell lines susceptible to the virus.

Massimo Pizzato, a HIV specialized virologist at the University of Trento and coordinator of the study, details how Nef is able to inhibit this protein and favor HIV infection: "This mechanism takes place in two stages. When HIV, stripped of the Nef protein, penetrates a cell to infect it, it succeeds without any problem. The virus then replicates normally. But when it comes out again to continue its destructive work in another cell, it takes a part of the infected cell membrane to build its own membrane. With it, it also carries the SERINC5 protein found on the membrane of the attacked cell. From then on, when the virus tries to infect a second cell, SERINC5 acts as an alarm signal and warns the cell that the pathogen is coming. The virus is therefore no longer able to penetrate." Nef, by inhibiting SERINC5, is therefore a crucial element for HIV infectivity.

Strengthening SERINC5

Usually, Nef is able to neutralize SERINC5. Nevertheless, the study shows that if SERINC5 is highly expressed, Nef is no longer able to counteract it, which greatly reduces the virus infection ability. The goal is therefore to reverse the balance of power to favor SERINC5. "SERINC5 is not the first antiretroviral factor discovered. For sure, we have identified a new element, but, most importantly, we deciphered a mechanism that works very differently from the others. Moreover, contrary to the antiretroviral factors previously discovered, which are activated by interferon (a protein substance produced by certain cells of the immune system in response to a pathogen), SERINC5 is expressed continuously in all cells of our immune system" states Federico Santoni.

"We now need to carry on working on this defensive mechanism to evaluate how to exploit this flaw in new therapeutic strategies, either by strengthening the presence of SERINC5 in all cells, or by modifying its structure to enable it to escape Nef inhibition. Long-term research!"