June 02, 2005
Virus Uses Tiny RNA to Evade the Immune System
In the latest version of the hide-and-seek game between pathogens
and the hosts they infect, researchers have found that a virus appears
to cloak itself with a recently discovered gene silencing device to
evade detection and destruction by immune cells.
The report by Howard Hughes Medical Institute (HHMI) researchers in
an article published in the June 2, 2005, issue of Nature may be
the first to show how a virus uses the gene silencing machinery for its
own infectious purposes.
“A popular notion is that the whole system of generating small RNAs was designed to be a defense by cells against viruses. Our study shows that a virus can also adapt it to evade the immune response.”
Donald Ganem
In people, plants, and worms, hundreds of tiny RNA molecules can
silence specific genes by interfering with larger messenger RNAs
(mRNAs). That interference prevents mRNAs from making proteins.
Scientists do not know which genes are hushed by the microRNAs in
people, but the new study bolsters growing evidence that the little
molecules can play important roles not only in normal human cells but
in infected cells as well.
“A popular notion is that the whole system of generating small
RNAs was designed to be a defense by cells against viruses. Our study
shows that a virus can also adapt it to evade the immune
response,” said HHMI investigator Don Ganem, who is at University
of California, San Francisco.
Ganem studies how viruses infect people and cause disease. When
scientists found that RNA interference appeared to be a basic and
widespread gene regulatory mechanism, “it became clear that such
a fundamental pathway could of course be pirated by a virus,”
said postdoctoral fellow Adam Grundhoff, co-first author of the
paper.
Thomas Tuschl, a newly selected HHMI investigator at The Rockefeller
University, had already reported the existence of several microRNAs
encoded by Epstein-Barr virus, although their functions were unknown.
Grundhoff and co-first author Christopher Sullivan, a postdoctoral
fellow in Ganem's lab, started their search for viral microRNAs with a
small virus, known as SV40, in the belief that its diminutive size
would make it easier to understand the functions of any microRNAs they
found.
SV40 is a relatively harmless monkey virus that can cause kidney
infections in its natural simian host. In rodents, however, it can
cause cancer. Although the SV40 genome has been found in some human
tumors, its role in human cancer has been debated. The virus is better
known as a model system that has greatly contributed to major
scientific advances about how genes work.
To launch their study, Grundhoff wrote a computer program to screen
the SV40 genome for possible microRNA precursors. MicroRNAs are made
from messenger RNA molecules with distinctive hairpin folds. The
hairpin structure is diced into a microRNA segment that works with
another complex to disable other messenger RNAs with complementary
sequences.
Among several dozen predicted microRNAs, the top candidate turned
out to be abundantly expressed in human cells infected with SV40.
Sullivan soon found the target of the plentiful SV40 microRNA. It
effectively targeted the messenger RNA for a protein known as T
antigen, leading to its cleavage. “SV40 may be the world's most
studied virus,” Sullivan said, “and T antigen is its most
studied part.”
When SV40 enters a cell, it produces T antigen, which functions to
trigger viral DNA replication. Unfortunately for the virus, T antigen
also serves as a target for immune (T) cells, which can destroy
infected cells and prevent the virus from spreading.
Conveniently, the microRNA that targets T antigen is made late in
the infectious cycle, just when T antigen is no longer essential for
virus replication. Further experiments showed that cytotoxic immune
cells were more likely to kill cells infected with a mutant virus that
cannot make the microRNA than the normal virus. Thus, microRNA-induced
reductions in T antigen expression promote escape from antiviral T
cells without affecting virus growth.
“Viruses can use the host RNA inference machinery, which is
often speculated to have evolved as an antiviral mechanism, to generate
small RNAs that serve their own purposes — the latest chapter in the
long cat-and-mouse game known to virologists as host-virus
coevolution,” the researchers conclude in their Nature
article.
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Jennifer Michalowski
