Systematic identification of host proteins involved in Human Cytomegalovirus replication, assembly and egress.

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Human cytomegalovirus (HCMV) is an important human pathogen, causing significant problems in transplant patients, where infection can increase the speed and severity of organ rejection as well as causing sever disease in its own right due to immunosuppression of patients. It is also the leading infectious cause of birth defects.There is currently no effective vaccine and available antiviral therapies have significant issues including side effects and development of resistance. The development of new antiviral treatments against HCMV is therefore a high priority for effective control in transplant and immunodeficient patients.Very few antivirals have been developed for use against HCMV since the licensing of Ganciclovir and, of these, the same viral genes are targeted, reducing the likely usefulness of these drugs against resistant strains. An alternative strategy for the development of novel antivirals involves targeting of host genes required by the virus for successful replication. The relatively low stability of viral genomes results in rapid development of resistant strains against antiviral drugs that directly target viral genes. Even before treatment, virus populations often contain strains with mutations that render them resistant to such drugs. In contrast developing resistance against drugs that target host genes would be far more complex, as the virus would need to gain mutations that would compensate for the loss of a required cellular gene. In many cases such mutations may not exist.By inhibiting individual host genes we have identified multiple host genes that are involved in human cytomegalovirus replication. We have shown that one of these host genes, VCP, is essential for one of the earliest steps in HCMV replication. Inhibition of this gene by a drug called NMS-873, resulted in complete inhibition of virus replication, validating this strategy for antiviral discovery and suggesting NMS-873 may be a potent future treatment option for HCMV infections.In this application we aim to further characterise how VCP is involved in HCMV replication as well as characterising additional host factors that may be potential drug targets for HCMV treatment. These findings will have important implications for the development of novel antiviral treatments, understanding the role of host factors in HCMV replication as well as understanding the function of host factors themselves.