||Researchers at the University
of Pennsylvania School of Medicine have identified
a new strategy that Kaposi’s Sarcoma Associated Herpesvirus
(KSHV) uses to dupe infected cells into replicating its
viral genome. This allows the virus to remain virtually
undetected by the body’s immune system.
||In the Robertson lab, 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, signaling
initiation of replication.
||With viral protein production eliminated,
the researchers discovered that KSHV DNA was capable of recruiting
the cellular replication machinery proteins and so autonomously
||The study was published in the August
issue of Cell Host and Microbe.
(PHILADELPHIA) – Researchers at the University
of Pennsylvania School of Medicine have identified
a new strategy that Kaposi’s
Sarcoma-Associated Herpesvirus (KSHV) uses to dupe infected cells
into replicating its viral genome. This allows the virus to remain
virtually undetected by the body’s immune
work suggested KSHV needed viral proteins to initiate replication,
but this is the first study to directly show that a section of
viral DNA can independently draw upon proteins within a host cell
to promote its own replication. The study was published in the
August issue of Cell
Host and Microbe.
“Without the necessary production of a viral protein, the virus
goes unidentified by the immune system while utilizing the host
replication machinery,” explains lead author Erle
Professor of Microbiology and
Program Leader of Tumor
Virology Program at
Penn’s Abramson Cancer
Center. Specifically, 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. Because viruses are asexual, they are
dependent upon the replication proteins, or “machinery” of
host cells to make new copies of their DNA material. 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 tumor viruses associated with human cancers do
require a viral protein to bind and initiate replication,” notes
In the Robertson
lab, 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, signaling initiation of replication. To test 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. With viral protein production eliminated, the
researchers discovered that KSHV DNA was capable of recruiting the cellular
replication machinery proteins and so autonomously replicate.
“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,” says Robertson. “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.”
In the future, Robertson and others plan to explore whether or not other
viruses are capable of replicating without utilizing the role of viral
proteins and learning more about cellular events that trigger replication.
Also, researchers will 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.
Subhash C. Verma, Ke
Choudhuri, and Murray A. Cotter,
all from Penn, were co-authors to this study.
This research was funded by the National
Cancer Institute, National
Institute of Allergy and Infectious Diseases, National
Institute of Dental and Craniofacial Research, The
Leukemia and Lymphoma Society, and
Tata Memorial Trust for Research in Leukemia.
The Abramson Cancer Center (ACC) of
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to providing state-of-the-art cancer care, the latest forms
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to our patients through clinical themes that developed in
the relentless pursuit to eliminate the pain and suffering
from cancer. In addition, the ACC is home to the 300 research
scientists who work relentlessly to determine the pathogenesis
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Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $7.8 billion enterprise.
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