Researchers discover a mechanism that blocks replication of a retrovirus

A team of scientists led by University of Georgia researchers has discovered a naturally occurring mechanism that blocks a critical step late in retrovirus replication. In the long term, the results could lead to the design of new therapeutic strategies or drugs against retroviruses, which cause diseases such as AIDS and certain leukemias.

Studying a transmissible lung cancer of sheep, the researchers found that the mechanism stops cancer-causing retroviruses from exiting host cells and spreading. Their findings shed new light on how retroviruses evolved and will help explain late steps in the retroviral life cycle.

The findings were published today in the Proceedings of the National Academy of Sciences. The team was led by Massimo Palmarini, a virologist at UGA’s College of Veterinary Medicine. Co-authors are Manuela Mura, Pablo Murcia and Marco Caporale of UGA; Thomas Spencer of Texas A&M University; and Kunio Nagashima and Alan Rein of the HIV Drug Resistance Program, National Cancer Institute in Frederick, Md.

This particular sheep lung cancer – called ovine pulmonary adenocarcinoma – led to the death of Dolly, the first cloned mammal. It is a chronic problem for the sheep industry in Europe and the United Kingdom.

“The cancer is caused by a retrovirus that passes from sheep to sheep like any other virus, such as the flu,” Palmarini said.

Like all viruses, retroviruses insert their genetic material into host cells and then force the host to make copies of the virus. Unlike other viruses, however, retroviruses permanently insert a copy of their genes into the genome of cells they invade.

During evolution, some retroviruses infected host germlines, underwent small changes that allowed the “alien” DNA to reside in the host genome permanently and be inherited by offspring. These so-called “endogenous retroviruses” are usually harmless and cannot orchestrate production of infective virus particles.

“Every sheep on the planet has endogenous retroviruses that are present in the genome like every other gene,” Palmarini said. “In fact, all animal species – humans included – have endogenous retroviruses.”

Sheep have some 20 different endogenous retroviruses related to the lung cancer-causing Jaagsiekte sheep retrovirus or JSRV.

Scientists believe that some endogenous retroviruses protect hosts by interfering with the infection by related disease-causing retroviruses.

Palmarini’s team discovered an endogenous retrovirus called enJS56A1 that makes viral particles that cannot escape from the cell. It also interferes with the cancer-causing retrovirus JSRV’s ability to exit host cells. The blocked escape route is attributed mainly to a single amino acid substitution in a protein that comprises the virus’s protective shell.

Other scientists have reported endogenous retroviruses that interfere with infective retrovirus replication at different points in early states of the cycle – specifically by blocking entry to the host cell or blocking before insertion of viral DNA into the host genome. This is the first report of an endogenous retrovirus interfering with the viral replication so late in the cycle.

Understanding how enJS56A1 functions could provide a model for designing new anti-retroviral therapies that work on cells already infected by retroviruses. Some common anti-retroviral drugs, such as reverse transcriptase inhibitors, function only immediately after the virus infects a new cell.

This research was funded by grants from the Georgia Cancer Coalition and the National Institutes of Health National Cancer Institute.

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