Restriction of DNA viruses by TRIM5a and ZAP / TRIM25 / KHNYN: mechanisms of restriction and viral evasion

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The cells of our body contain proteins that mediate defense against virus infection. Such proteins are called restriction factors, because their actions restrict virus replication. Examples of restriction factors are proteins called TRIM5alpha, ZAP, TRIM25 and KHNYN. Hitherto, it was thought that the action of these restriction factors was directed against mostly viruses that have RNA, rather than DNA, genomes. For instance, TRIM5alpha is well known as a restriction factor for retroviruses, such as HIV, and ZAP, TRIM25 and KHNYN are active against RNA viruses that have genomes rich in the ribonucleotides (RNA building blocks) C followed by G. However, we have discovered that these restriction factors are also active against vaccinia virus, a large DNA virus that was used as the vaccine to eradicate smallpox. Furthermore, we have found that these 4 cellular proteins are all degraded during vaccinia virus infection so enabling the virus to escape their anti-viral action. Lastly, as found with HIV, another cellular protein, called cyclophilin A, is incorporated into vaccinia virus particles where it helps protect against the anti-viral effect of TRIM5alpha. This protective role of cyclophilin A can be inhibited by a drug, cyclosporine A, which provides protection against the antiviral activity of TRIM5alpha.This project will study how these restriction factors work against vaccinia virus, and the countermeasures that vaccinia virus deploys to diminish their impact. The project has two parts. In the first, we will determine how these host proteins restrict vaccinia virus replication and at what stage during virus infection they do this. The project will also investigate if these restriction factors affect the replication of other large DNA viruses such as herpes simplex virus, the cause of cold sores, and human cytomegalovirus, a cause of disease during pregnancy and during immunosuppression, such as following transplant surgery. In the second part, to run in parallel, the project will investigate the countermeasures that vaccinia virus has evolved to escape or neutralise the antiviral activity of these restriction factors. For instance, how does vaccinia virus enable the packaging of cyclophilin A into virus particles to protect against TRIM5alpha, and how does vaccinia virus induce the degradation of these host restriction factors. Which vaccinia virus proteins are needed for this and which cellular proteins do they interact with to mediate this targeted destruction?Overall, this project will enhance our understanding of the interactions between viruses and the cells they infection that ultimately may lead to the development of safer attenuated vaccines and / or the development of drugs to treat virus infections.