18/12/2012

Discovered how the AIDS virus enters key immune cells

Scientists from the AIDS Research Institute IrsiCaixa, funded by “la Caixa” Foundation and the Health Department of the government Generalitat de Catalunya (the autonomous Catalan government), have identified how HIV, the virus that causes AIDS, enters the cells of the immune system responsible for the dispersion of the virus inside the organism. This mechanism was an enigma that the scientific community had been trying to solve during the last years.
The new work identifies the molecule located on these cells that is responsible for HIV capture. It allows the internalization of the virus within these cells which are called dendritic cells, and act as a “Trojan horse” dispersing the virus inside the organism.
The discovery opens the doors to a new family of drugs against AIDS that could block these molecules. The new drugs would improve the efficacy of the current treatments, which do not act on this mechanism of dispersion of the virus.
The study has just been published (yesterday evening, 18th December) in the international scientific journal PLoS Biology, and has been performed within the HIVACAT Program for the research and development of a vaccine against AIDS.

One of the reasons why we still do not have a cure for HIV infection yet is that the virus infects cells of the immune system that activate the response that should stop infection. In concrete terms, the main HIV targets are a sort of white cells named CD4 T lymphocytes, so called because they have the protein CD4 on their membrane.

While we have more than 20 different drugs available today in the market, all of them act blocking the cycle that HIV follows to infect those CD4 T lymphocytes, but do not cure because they do not manage to eliminate all the viruses from the organism. One of the possible explanations for that fact is that the available treatments do not fully act on another kind of immune cells, called dendritic cells, where HIV also penetrates and remains almost fully infectious. Dendritic cells are responsible for activating the immune response, but when they do it, they also infect CD4 T lymphocytes in parallel. Therefore, the proliferation of the infection is more efficient when dendritic cells harboring viruses are around.

Now, scientists from the AIDS Research Institute IrsiCaixa, funded by “la Caixa” Foundation and the Health Department of the Generalitat de Catalunya (the autonomous catalan government), have identified the entry door that HIV uses to hide into dendritic cells, an enigma that the scientific community had been trying to solve for years. The work has just been published in the international scientific journal PLoS Biology, and it has been supported by the HIVACAT Program for the research and development of a vaccine against AIDS.

Siglec-1 is the molecule that can be found on the surface of dendritic cells that allows the entry of HIV into cells. It acts as a gateway for HIV to mature dendritic cells when are joined by the gangliosides of the virus, functioning as a key. Thus, dendritic cells accumulate large amounts of virus inside and become Trojan horses, allowing the infection of the CD4 + T cells, the main target of HIV, and contributing to spread HIV through the body.

Javier Martínez-Picado: “We had the key and now we have found the lock. The enigma is solved"

These results are the latest milestone of a research line leaded by the ICREA research professor at IrsiCaixa Javier Martínez-Picado and the IrsiCaixa researcher Nuria Izquierdo-Useros, in collaboration with two research groups, one from the Heidelberg University, in Germany, coordinated by professor Hans-Georg Kräusslich and another one from the University of Lausanne, in Switzerland, leaded by Amalio Telenti. As a result of this collaboration, another paper was also published on PLoS Biology last April, where they had identified one molecule, called ganglioside, located on the surface of HIV and responsible for its entrance into the dendritic cells. The new results discover which is the molecule on the surface of dendritic cells that captures HIV and allows for spreading through the organism. According to the researcher Javier Martínez-Picado “we had the key and now we have found the lock. The enigma is solved. Now we are already working in the development of a drug that could block this process to improve the efficacy of the current existing treatments against AIDS”.

As the researcher Nuria Izquierdo-Useros highlights, “we have observed that the protein that acts as a lock for the entrance of HIV could also facilitate the entrance of other viruses, and therefore our results could also lead to the development of treatments for other infections that exploit this mechanism of dispersion”.

In order to identify the precise molecule located on the membrane of the dendritic cells capable of capturing HIV, the researchers studied one family of proteins that are present on the surface of those cells, called Siglecs. It is known that those proteins bind to the gangliosides on the HIV. Scientists did then experiments mixing virus with dendritic cells that displayed different quantities of Siglec-1. By these means, they could conclude that when the quantity of Siglec-1 increased on the surface of dendritic cells, those cells captured more viruses, which in turn allowed for enhanced transmission of viruses to target CD4 T lymphocytes that became highly infected. They also performed another experiment where they inhibited the Siglec-1 protein. They did so either coupling it with antibodies or blocking the expression of the corresponding gene. Under these circumstances, the dendritic cells lost their capacity to capture HIV and, what is more important; they also lost their ability to transfer HIV to CD4 T lymphocytes. With all these data, the scientists concluded that Siglec-1 is the molecule responsible for HIV entrance into the dendritic cells, allowing for viral transmission to CD4 T lymphocytes and could therefore become a new therapeutic target.

Three-dimensional reconstruction of a mature dendritic cell (in gray) where HIV is stored (in red) and the new receptor identified, Siglec-1 (in green). The yellow figure shows the moment when the virus (in red) and the receptor (in green) are in the same compartment within the cell. In blue, the nucleus of the dendritic cell.

About dendritic cells, the “Trojan Horse” of the AIDS virus
If a pathogen enters our body, dendritic cells play a key role activating the immune response. Dendritic cells operate patrolling the body and capturing the infectious agents that invade us to isolate pathogenic molecules and deliver them to T cells, wich are the ones that destroy microbes or other cells that are already infected. However, HIV takes advantage of dendritic cells and sneaks inside them, without actually infecting them, as a way to reach their main targets, the CD4 T lymphocytes. Thus, dendritic cells act as true "Trojan horses", as they concentrate the virus in the area of contact with CD4 T cells, favoring their infection, instead of starting an adequate immune response against the virus. The present discovery provides new insights into how HIV enters dendritic cells, how it escapes from the usual pathways of pathogen degradation and how it creates an ideal scenario for infecting new target cells.

Izquierdo-Useros N, Lorizate M, Puertas MC, Rodriguez-Plata MT, Zangger N, et al. (2012) "Siglec-1 Is a Novel Dendritic Cell Receptor That Mediates HIV-1 Trans-Infection Through Recognition of Viral Membrane Gangliosides". PLoS Biol 10(12): e1001448. doi:10.1371/journal.pbio.1001448

2012 Izquierdo-Useros et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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High ressolution pictures here. Images: Nuria Izquierdo-Useros