Wednesday, December 18, 2013

Myeloid Dendritic Cells Enhance HIV Latency in T Cells

Diagram of the HIV virus

The Human Immunodeficiency Virus commonly known as HIV in the last 30 years has become a worldwide epidemic affecting approximately 23 million people with an additional 4 million cases annually.  This virus systematically disrupts and destroys the host immune system and is the direct precursor to Acquired Immunodeficiency Syndrome or AIDS.  Despite years of intense scientific research there is no cure or vaccine for HIV.  The current form of treatment is continual use of anti-retroviral drugs which can help to keep HIV at bay but are expensive and have side effects.  The virus itself invades a number of different immune cells and inserts its DNA into the DNA of the cell causing it to produce more of the HIV virus.  The virus itself is also toxic to subsets of these cells known as CD4+ T cells which die after the virus has replicated within the cell.  The destruction of these CD4+ T cells mediates the inability of the immune system to fight off other pathogens. 
                A major problem in combating HIV is that after the virus infects a cell it sometimes lays dormant in the cells to be replicated later.  In this case the virus is not immediately killing the cell but it in the meantime escapes normal processes of destruction.  This viral latency allows the virus to remain in the immune system undetected and escape destruction by other immune cells or anti-retroviral therapy.  Despite this common occurrence, the mechanisms underlying this process are relatively unknown.  However, a recent paper has partially uncovered how some CD4+ T cells are latently infected with the HIV virus.  A paper published this month by Evans et al. has demonstrated the myeloid dendritic cells are responsible for the latent infection of inactivated CD4+ T cells.  In this study, researchers co-cultured inactive CD4+ T cells with different types of infected dendritic cells to see whether they would cause a latent infection and if so which dendritic cells specifically.  The resting CD4+ cells were given a green fluorescent protein which gave off a green light when the cells were actively infected with the HIV-like virus.  The researchers then separated out the non-glowing cells which were not actively infected and further examined those.  When these CD4+ T cells were stimulated a small percentage of them turned green when they had not before, indicating that they contained the virus previously but it was not active and thus the virus was in a latent state.  This process allowed scientists to culture the CD4+ T cells with other cells or chemicals to see what factors caused the cells to have an active or latent infection.  Given this, it was soon discovered that infected myeloid dendritic cells caused a latent infection but not other types of dendritic cells.  Myeloid DCs are cells which migrate in the body and encounter pathogens.  These pathogens are then engulfed, chopped up by enzymes within the cell, and represented on the surface of the cell so that T cells may encounter the antigen and form an immune response against it.   Intriguingly it was previously thought that chemicals released by DCs or the environment called cytokines might be playing a role in the process, however, when the chemicals from the DC-T cell interaction were removed and cultured with new CD4+ T cells they did not develop a latent infection indicating that the myeloid DCs must have a physical connection to the T cells for this process to occur.  The connection between the two is an immunological synapse which involves numerous molecular adhesion molecules such as LFA-1 or ICAM.  The same study found that when they blocked these adhesion proteins there was a reduced effect of infection latency among CD4+ T cells but it did not eliminate latent infection completely so more than these two adhesion molecules must be involved.  These would be new potential targets for anti-retrovirals or other drugs.
Depiction of HIV spread from a DC to a T cell

                This most recent paper is one small step towards finding a solution for HIV.  While we are still a long way from developing a cure, these papers help to implicate other sources for drug therapy.  It also brings additional questions such as: How do HIV buds spread across this immunological connection?  Do the buds need to be in a certain proximity to the CD4+ T cells?  And, How do we prevent this adhesion without blocking the normal necessary process of adhesion?  Only time will tell for these questions but for now we are one step closer.

1.       Evans, V. A., Kumar, N., Filali, A., Procopio, F. A., Yegorov, O., Goulet, J. P., . . . Lewin, S. R. (2013). Myeloid dendritic cells induce HIV-1 latency in non-proliferating CD4(+) T cells. PLoS Pathogens, 9(12), e1003799.
Additional Sources:
     1. Coleman, C. M., Gelais, C. S., & Wu, L. (2013). Cellular and viral mechanisms of HIV-1 transmission mediated by dendritic cells. Advances in Experimental Medicine and Biology, 762, 109-130

       2.   Gopinath, A., Xu, G., Ress, D., Oktem, O., Subramaniam, S., & Bajaj, C. (2012). Shape-based   regularization of electron tomographic reconstruction. IEEE Transactions on Medical Imaging, 31(12), 2241-2252. doi:10.1109/TMI.2012.2214229; 10.1109/TMI.2012.2214229 

             3.     Pretorius, E., Oberholzer, H. M., Smit, E., Steyn, E., Briedenhann, S., & Franz, C. R. (2008). Ultrastructural changes in platelet aggregates of HIV patients: A scanning electron microscopy study. Ultrastructural Pathology, 32(3), 75-79. doi:10.1080/01913120802034793; 10.1080/01913120802034793

4.  Steinman, R. M., & Inaba, K. (1999). Myeloid dendritic cells. Journal of Leukocyte Biology, 66(2), 205-208.

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