University of Pennsylvania School of Medicine scientists have identified a unique mechanism of Kaposi's Sarcoma-Associated Herpesvirus (KSHV). Here, the virus dupes infected cells into replicating its viral genome, without being detected by the body's immune system.
Previous studies had suggested that KSHV needed viral proteins to initiate replication. The new study, however, shows that a section of viral DNA can independently draw upon proteins within a host cell to promote its own replication.
Advertisement"Without the necessary production of a viral protein, the virus goes unidentified by the immune system while utilizing the host cell's replication machinery," said the study's lead author, Dr. Erle Robertson, Professor of Microbiology and Director of Tumor Virology Training at Penn's Abramson Cancer Center.
Published in the journal Cell Host and Microbe, the study suggests that KSHV can overwhelm a weakened immune system, resulting in the development of Kaposi's sarcoma and other diseases of the lymphocytes.
A virus, comprised of only its genetic code wrapped in a protective protein cover, will infect a cell by penetrating its membrane and releasing the viral genome into the cell. The viruses' asexual nature makes them dependent upon the replication proteins.
In order to access the cellular proteins needed to replicate, Robertson says most scientists believed viruses must produce a viral protein.
"Our findings now break the long standing dogma of the virology field, which held that tumour viruses associated with human cancers do require a viral protein to bind and initiate replication," notes Robertson.
Previous studies of human cells infected with KSHV led researchers to locate a gene that codes for a viral protein called latency-associated nuclear antigen (LANA) that binds to viral DNA, signalling initiation of replication.
For testing whether or not KSHV replication was solely dependent upon LANA, the researchers eliminated the production of LANA by KSHV and introduced the LANA-free expression system into host cells.
It was found that KSHV DNA was capable of recruiting the cellular replication machinery proteins, and thereby replicating autonomously.
"Once again, a virus has broken the mold in terms of our understanding of cellular processes and is teaching us new tricks about their ability to utilize the cellular mechanism for replication. By studying how viruses usurp this cellular function to their advantage, we can learn new bits of information about the mechanism of cellular replication in humans," says Robertson.
The researchers are now planning to explore whether or not other viruses are capable of replicating without utilizing the role of viral proteins, and to learn more about cellular events that trigger replication.
They will also look to identify ways to block KSHV from replicating without blocking cellular replication in order to stop the virus before it has a chance to overwhelm the immune system, and progress into a disease.
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