Thursday, May 10, 2012
Hijacking dendritic cells
Dendritic cells are antigen-presenting cells: their main function is to patrol in search for "foreign objects" (the antigens). When it finds an antigen, the dendritic cell "chops it up" in fragments that are then presented to its surface. In more technical terms, it takes up the antigen by either phagocytosis or receptor-mediated endocytosis and transfers it to the cytosol, where further degradation may occur via proteosome. From here the resulting antigen peptides enter the endoplasmic reticulum and, ultimately, are exposed on the cell surface. At this point the dendritic cell migrates to the lymph nodes, which are rich in T-cells. The antigen fragments it carries on its surface are like red flags: once a T-cell recognizes a specific fragment, it gets "activated" and new T-cells with the same antigen specificity are created in order to mount an immune response against the invader.
Now, as you know, HIV infects preferentially T-cells. However, as a sexually transmitted virus, it first enters the body through the genital mucosa. How does the virus find T-cells from there? Easy. It highjacks dendritic cells and takes a ride to the lymph nodes, where the T-cells are.
But wait... the dendritic cell is supposed to kill the virus, not give it a ride...
Unfortunately, HIV has developed a mechanism that allows it to escape the usual degradation process inside the dendritic cell. It is capable of hitchhiking the dendritic cell without compromising its infectivity by residing "in an invaginated domain within the cells that is both contiguous with the plasma membrane and distinct from classical endocytic vesicles ." These are small membrane vesicles that are referred to as exosomes. They may be released in the extracellular milieu, following fusion of the multivesicular bodies with the plasma membrane. Once inside the dendritic cell, the virus can infect a T-cell via a mechanism called trans-infection, where the virus is passed from one cell to the other through the release/fusion mechanism of the exosome.
As you can imagine, these mechanisms are very interesting to study because if we could block the "highjacking" of the dendritic cells at the mucosa level, we could possibly stop the virus from spreading to the T-cells and initiate the infection. A team of researchers from Spain and Germany have studied this mechanism extensively. In a 2010 paper , Izquierdo-Useros et al. suggested that mature dendritic cell trans-infection could play an important role in augmenting "viral dissemination in the lymphoid tissue and significantly contribute to HIV disease progression." Mature dendritic cell encounter many T-cells every hour, with contacts that last several minutes, and as a consequence they have the potential to infect a broad number of T-cells. This could explain why HIV productive infection is more likely in subjects with a pre-existing sexual infection: the pre-existing mucosal inflammation could be responsible for the mobilization of a higher number of dendritic cells, which, in turn, could favor the spread of the HIV virus.
In a paper published last month , the research team showed that a particular class of lipids on the HIV surface favors the uptake of the virus into the dendritic cells. These lipids, called gangliosides, are a group of glycosphingolipids that are comprised of a ceramide linked to several oligosaccharide chains. They are basic components of the host cell’s plasma membrane, and they get incorporated into the viral envelope (the outer shell of the virus) when a new viral particles buds out of the cell. Izquierdo-Useros et al.  used artificial virus-like particle to show that only viruses with these lipids present on their surface were able to get into the dendritic cells.
Together, these findings pave new ways for novel strategies to block the spread of the HIV virus in the body, as well as a possible dendritic cell based vaccine.
Edit: As I was browsing the latest PNAS issue, I noticed an independent paper that reports the same finding that glycosphingolipid GM3 on the HIV-1 envelope allows for viral capture by mature dendritic cells. I've included the citation below .
 Izquierdo-Useros, N., Naranjo-Gómez, M., Erkizia, I., Puertas, M., Borràs, F., Blanco, J., & Martinez-Picado, J. (2010). HIV and Mature Dendritic Cells: Trojan Exosomes Riding the Trojan Horse? PLoS Pathogens, 6 (3) DOI: 10.1371/journal.ppat.1000740
 Izquierdo-Useros, N., Lorizate, M., Contreras, F., Rodriguez-Plata, M., Glass, B., Erkizia, I., Prado, J., Casas, J., Fabriàs, G., Kräusslich, H., & Martinez-Picado, J. (2012). Sialyllactose in Viral Membrane Gangliosides Is a Novel Molecular Recognition Pattern for Mature Dendritic Cell Capture of HIV-1 PLoS Biology, 10 (4) DOI: 10.1371/journal.pbio.1001315.
 Puryear, W., Yu, X., Ramirez, N., Reinhard, B., & Gummuluru, S. (2012). HIV-1 incorporation of host-cell-derived glycosphingolipid GM3 allows for capture by mature dendritic cells Proceedings of the National Academy of Sciences, 109 (19), 7475-7480 DOI: 10.1073/pnas.1201104109