Researchers identify molecular link between viral infection and cancer susceptibility
A Portuguese-US research team has discovered a new molecular mechanism that enables gamma herpes viruses to chronically infect patients. Their research also offers a greater understanding of why these patients are more likely to suffer from lymphocyte (white blood cell) cancer lymphoma; this is especially evident in cases of immunodeficiency. The results of the study were published in the online edition of The EMBO Journal.
The researchers' findings demonstrate that a protein from the gamma herpes viruses, called ORF73, mimics the host molecular machinery to inhibit NF-kB on infected lymphocytes. NF-kB is a protein complex that acts as a transcription factor and is involved in cellular responses to various stimuli including death and proliferation. The discovery also sheds light on how this process sets the stage for the development of lymphomas.
'The ORF73 protein from the lymphotropic gamma herpes virus MuHV-4 is a strong terminator of NF-kB-dependent transcription. Several viral proteins have been shown to interfere with the NF-kB pathway,' the authors wrote in their paper. 'The mechanism involves the assembly by ORF73 of an EC5S E3 ubiquitin-ligase. This complex targets nuclear-activated RelA for poly-ubiquitination and subsequent proteasomal degradation.'
The researchers explained that if NF-kB inhibition in gamma herpes virus-infected patients with lymphomas is confirmed, drugs capable of saving the molecule could effectively decrease the chances of someone developing lymphomas.
Gamma herpes viruses infect white blood cells (B or T lymphocytes) remaining latent in the lymphoid tissues as an asymptomatic chronic infection, but can also trigger the appearance of lymphomas. According to the researchers, gamma herpes viruses include the common Epstein-Barr virus, the causative agent of infectious mononucleosis, and Kaposi's sarcoma-associated herpes virus, a cancer affecting AIDS patients.
The relationship between chronic lymphocyte infection and lymphomas remains a mystery because there is very little information about the mechanisms behind the virus/infected lymphocytes interaction, the team explained. But they pointed out that the viral manipulation of the host molecular machinery wreaks havoc with the normal controls of the cells, which, in turn, raises the risk of cancer. According to them, this is a plausible reason because viruses cannot self-reproduce and are forced to 'hijack' the infected cells' molecular machinery so as to split away and spread infection.
'These findings demonstrate that viral inhibition of NF-kB activity in latently infected germinal centre centroblasts is critical for the establishment of a gamma herpes virus persistent infection, underscoring the physiological importance of proteasomal degradation of RelA/NF-kB as a regulatory mechanism of this signalling pathway,' the authors wrote.
Participating in the study were the Institutes of Microbiology and of Molecular Medicine at the University of Lisbon (Portugal), the Gulbenkian Science Institute (Portugal) and the Weill Medical College of Cornell University (US).