The scientific community has spent years trying to elucidate the mechanism of entry of the HIV virus into immune system cells termed dendritic cells, which contributes to the spread of the virus in the body. For years, different mechanisms have been suggested, but finally scientists at the IrsiCaixa Institute for AIDS Research, promoted jointly by the "la Caixa" Foundation and the Department of Health of the Generalitat de Catalunya, have discovered the molecule responsible for the entry of the virus into these cells. This finding, to be published next April 24 in the international journal PLoS Biology, which has been the subject of a European patent application filed in December 2011 by Esteve, IrsiCaixa and ICREA, opens the door to a new family of drugs against AIDS capable of blocking this molecule, thus preventing treatment resistance to current drug therapies.
Previous studies pointed to another molecule on the surface of the HIV virus as responsible for the binding of the virus to dendritic cells. However, the study of IrsiCaixa clarifies this finding and shows that the contribution of such a molecule to the process of spreading of the virus carried out by dendritic cells is only very small, as even blocking and eliminating this molecule from the surface of the HIV, the virus manages to penetrate the dendritic cells.
This study, coordinated by ICREA researcher of IrsiCaixa Javier Martinez-Picado, has had the collaboration of the University of Heidelberg in Germany and the Institute of Advanced Chemistry of Catalonia (IQAC) of the Higher Council for Scientific Research (CSIC).
The study has identified molecules on the surface of the HIV virus, consisting essentially of a sialic acid bound to a sugar or glucid, which in turn is anchored to a lipid, and which are called gangliosides. This type of molecules is found in high concentration in the membranes of nerve cells and in lesser amounts in the membranes of other cells. HIV selectively captures these molecules from cell membranes during the process of replication in an infected cell.
Scientists have altered the composition of gangliosides on the surface of artificial viruses and liposomes (spherical vesicles formed by the components of cell membranes). When these particles entered into contact with dendritic cells, scientist demonstrated that only vesicles with specific gangliosides on their surface could enter the cells. Finally, the researchers showed that eliminating gangliosides directly from the AIDS virus prevents dendritic cells from capturing and internalizing HIV-1 thus also preventing the infection of their natural targets, CD4 T lymphocytes.
According to IrsiCaixa researcher, Nuria Izquierdo, "this has demonstrated that gangliosides are the key to the entry of HIV into this type of cells and that their mechanism of entry is not dependent on viral proteins, but mainly on the presence of these molecules”.
The study was funded by the National R & D+ i Program and the HIVACAT AIDS Vaccine Research and Development Project, which already has several vaccine candidates. The HIVACAT project is developed through a public-private consortium unprecedented in Spain that puts our country in the international forefront of research carried out in this area. Composed of two international reference research centers in AIDS, such as IrsiCaixa and the Department of Infectious Diseases and AIDS of Hospital Clínic de Barcelona, HIVACAT carries out research work on the development of the new vaccine against HIV in coordination with Esteve and with the support of the "la Caixa" Foundation and the departments of Health and Economy and Knowledge of the Generalitat de Catalunya.
About dendritic cells, the “Trojan Horse” of the AIDS virus
If a pathogen enters our body, dendritic cells play a key role in the activation of the immune response. Its function is to patrol the body, capturing the infectious agents that invade us, isolate their molecules and deliver them to T cells, cells that specifically destroy microbes and cells already infected. However, HIV takes advantage of dendritic cells to take refuge inside without actually infecting them, as a way to get to their main targets, 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 HIV. The present discovery provides new insights into how HIV enters dendritic cells, how it escapes from the usual pathway of degradation of pathogens and creates an ideal scenario for infection of new cells and disease progression.
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© Olga Esteban and Nuria Izquierdo-Useros
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