"Jumping genes": new target for body's innate immune protection system against viruses

March 7, 2006

“Jumping genes”: new target for body’s innate immune protection system against viruses

March 7, 2006

La Jolla, CA – When HIV and other retroviruses invade a cell in the human body, a fierce battle ensues between the intruder and the cell’s defense team: members of the APOBEC family, a handful of closely related antiviral proteins that try to disarm the invading virus by scrambling its genetic information.

But not every family member pitches in. One family member, APOBEC3A or A3A, is conspicuously absent when other APOBECs are battling HIV. Now, scientists at the Salk Institute for Biological Studies have discovered that A3A, the falsely accused deserter, specializes in defending against two different kinds of invaders: “jumping genes,” pieces of DNA that can leap from one place in the human genome to another, and Adeno-associated virus (AAV), a tiny harmless virus very different from HIV.

The scientists report their findings in the current online edition of Current Biology.

“People thought that this particular family member didn’t warrant a lot of attention because it didn’t seem to do anything. But it turned out to have a very powerful effect when we looked in the right place,” said Nathaniel Landau, Ph.D., professor in the Infectious Disease Laboratory at the Salk.

And the lab of his colleague Matthew Weitzman, Ph.D., at the Salk’s Laboratory of Genetics turned out to be the perfect place.

“Together, we could not only assign a new function to a APOBEC family member that previously had none, but we also expanded the repertoire of different types of viruses against which this innate antiviral system is effective,” said associate professor Weitzman, Ph.D., who studies virus-host interactions using Adeno-associated virus or AAV. “This implies that different members of the APOBEC family may have evolved to defend the cell against different types of parasites,” he added.

To disarm the virus, members of the APOBEC family edit the genetic information carried by the virus, mutating it so badly that the virus can’t function any longer. To do this, the APOBEC proteins remove an essential chemical group from cytosine, one of the four building blocks of DNA that spell out the genetic code, turning the DNA’s message into gibberish.

Throughout evolution, cells had to defend themselves against the attack of viruses and “jumping genes,” also called mobile genetic elements and either side could win these battles. Nowadays, mobile elements are mostly inactive, but since they successfully invaded the human genome millions of years ago, they are part of each person’s genetic code, and their remnants account for more than 45 percent of our DNA. “In the case of HIV, the virus won the battle and it will spread through the human population until human ingenuity can outwit it,” said Landau.

One group of “jumping genes” called retrotransposons is closely related to HIV but unlike their feared cousin have lost the ability to escape from their host cell. Marooned inside, they can only move via a “copy and paste” mechanism, taking up ever more space in their host’s genome.

If allowed to multiply unchecked, these “jumping genes” can inactivate essential genes or activate cancer-causing genes. “In mice, you see the evolutionary hallmarks of the cells’ struggle to keep these elements in check. Many existing copies of retrotransposons have been inactivated by APOBEC generated mutations,” said Landau.

The tiny Adeno-associated virus depends on the help of the larger Adenovirus to multiply and does no harm in humans. “We think that a pathogenic virus that is like AAV could be the real target of 3A,” said Weitzman. “One candidate might be parvovirus B19, which infects red blood cells and causes Erythema infectiosum (Fifth disease or ‘slapped cheek syndrome’) in children,” he explained.

Unlike other members of the APOBEC family, A3A has no effect on HIV or other retroviruses. “One explanation could be that 3A appears to be active in the cell’s nucleus where mobile elements and AAV multiply but the APOBEC-sensitive step during HIV replication happens outside the nucleus in the cytoplasm,” speculates Landau.

Researchers who contributed to the work include co-first author Hui Chen and postdoctoral researchers Quin Yu and Jody Chou in the Infectious Disease Laboratory, co-first author Caroline E. Lilley as well as Darwin V. Lee and I?igo Narvaiza in the Laboratory of Genetics.

加利福尼亚州拉霍亚的索尔克生物学研究所（Salk Institute for Biological Studies）是一个独立的非营利组织，致力于在生命科学领域做出基础性发现，改善人类健康，并培养未来的研究人员。其脊髓灰质炎疫苗几乎根除了1955年令人衰弱的脊髓灰质炎疾病的乔纳斯·索尔克医学博士于1965年创立了该研究所，得到了圣地亚哥市赠送的土地以及“March of Dimes”组织的财政支持。.