Virus uses RNA cloak for immune attack
itself with a recently discovered gene-silencing device to evade
detection and destruction by immune cells. The study is the first
to show how a virus uses the gene silencing machinery for its own
infectious purposes providing a target for drug treatment.
The study shows that a virus can adapt to evade the immune response going against the widely held belief that the whole system of generating small RNAs was designed to be a defence by cells against viruses.
In humans, 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.
Previous studies have shown that RNA interference appeared to be a basic and widespread gene regulatory mechanism. The scientists involved in the study postulated that a virus could hijack such a pathway.
In this latest study, investigators from the Howard Hughes Medical Institute (HHMI), used a computer program to screen a 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.
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 tumours, 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.
Among several dozen predicted microRNAs, the top candidate turned out to be abundantly expressed in human cells infected with SV40.
Christopher Sullivan, a postdoctoral fellow at the Rockefeller University, found the SV40 microRNA 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."
Sullivan, along with HHMI investigator Don Ganem, who is at University of California, San Francisco, discovered that 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 article.
The study appears in the June 2, 2005, issue of Nature.
