The research, just published in the advance online edition of The Embo Journal, reveals how these viruses mimic the host molecular machinery to shutdown NF-kB –a key regulatory protein complex involved in cell division and death – on infected lymphocytes, and how this - probably by disrupting the cells normal regulatory systems - creates the conditions for the development of lymphomas.
A crucial implication of the discovery - if gamma herpes virus-infected patients with lymphomas are confirmed to shutdown their NF-kB– is that drugs to rescue this molecule, which are available in the market, will be able to reduce the chances of lymphomas in these patients.
Gamma herpes viruses specifically infect white blood cells (B or T lymphocytes) often remaining latent in the lymphoid tissues as an asymptomatic chronic infection but, sometimes - particularly in immune compromised individuals such as transplant or AIDS patients – can lead to the appearance of lymphomas. Examples of gamma herpes viruses include the Epstein-BarrVirus - responsible for mononucleosis or glandular fever and linked to the endemic Burkitt lymphoma, the most common childhood cancer in many parts of Africa - and the Kaposi’s sarcoma-associated herpes virus, a type of cancer characteristic of AIDS patients.
This association between the chronic lymphocyte infection and lymphomas - a cancer where lymphocytes divide abnormally and without control - is not understood as not much is known abut the mechanisms behind the virus/infected lymphocytes interaction. The most logical explanation, however – since viruses do not have the means to reproduce themselves and need to hijack the infected cells’ molecular machinery in order to divide and spread infection – is that the viral manipulation of the host molecular machinery disturbs the cells’ normal controls leading to an increased risk of cancer.
In order to try and understand this Lénia Rodrigues, J Pedro Simas and colleagues at the Institute of Molecular Medicine and the Gulbenkian Institute in Lisbon Portugal and the Weill Medical College of Cornell University, New York, USA decided to look into NF-kB, a known target for many viruses but also a key regulatory molecule of genes involved in cell death and proliferation and known, when defective, to be linked to cancer. Because the establishment of a chronic infection depends on the capacity of the virus to remain latent in the organism, the researchers looked at NF-kB within the host germinal centres, which are the areas of the lymph nodes where B cells divide but also the place where the gamma herpes virus is known to stay latent.
What Rodrigues, Simas and colleagues discovered was a totally new viral “hijacking” mechanism where a protein from gamma herpes viruses - called ORFT3 - mimics a host NF-kB regulator to shutdown NF-kB. In fact, when the cells are resting, NF-kB molecules are maintained in the cell cytoplasm away from the nucleus where the chromosomes - with all the genes that NF-kB regulates – are found. When NF-kB needs to be activated - for example when an immune response is necessary - the inhibitory molecules are destroyed and NF-kB can then migrate into the nucleus where it specifically activates its target genes. ORF73 was shown to shutdown NF-kB in the nucleus by destroying a subunit of NF-kB by a similar mechanism to the one used to eliminate the inhibitory molecules.
In a second set of experiments Rodrigues and colleagues showed that gamma herpes viruses with defective ORF73 were incapable of expanding within the infected B cells, or maintain a persistent infection, highlighting the importance of this novel viral NF-kB shutdown mechanism for the establishment of the chronic infection (and the accompanying tumour susceptibility).
So NF-kB shutdown by OFR73 results in the proliferation of B cells, which allows the virus to divide, spreading the infection throughout the germinal centres where it could then stay latent. Rodrigues and colleagues believe that during the normal process of B cell differentiation NF-kB needs to be temporarily shutdown - after a prior activation that allows the molecule to migrate into the nucleus - to let the cells divide and it is this period that ORF73 mimics. This explanation agrees with results showing that constant NF-kB inhibition from the most initial stages of viral infection impairs the establishment of latency, as well as with Rodrigues, Simas and colleagues’ findings that ORF73 targets NF-kB in the nucleus.
Rodrigues, Simas and colleagues’ study has several important implications including a better understanding of how herpes viruses persist in the host and their interactions with the infected system.
But, and most crucially, it shows a new molecular link between viral infections and the appearance of cancer. This can now be further researched and, if confirmed in patients, become an important therapeutic target to prevent the appearance of potentially fatal lymphomas in infected patients.
Article: “Termination of NF-κB activity through a gammaherpesvirus protein that assembles an EC5S ubiquitin-ligase”, The Embo Journal – 2009 Online Early Edition doi: 10.1038/emboj.2009.74.
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