Mode of action of human cytomegalovirus protein pp71

Lead Research Organisation: MRC Virology Unit

Abstract

Human cytomegalovirus (HCMV) causes a variety of human diseases. The majority of the population in Western society harbour the virus without noticeable symptoms, but HCMV is a serious problem in situations where an individuals immunity is damaged. This is a problem for organ transplant recipients, where the virus multiplies in the donated organ and causes rejection, and in AIDS patients, where HCMV infection can result in a serious, widespread infection. If contracted by mothers during pregnancy, HCMV can infect the foetus and cause major permanent damage. The drug ganciclovir is active against HCMV, but it must be administered continuously to prevent the virus from resuming infection. Long term ganciclovir therapy is undesirable due to side effects.||We are trying to understand how HCMV starts its infection of the host, and have concentrated our efforts on one part of the virus that is important at this early stage. The work is currently a detailed study in the laboratory, using specialised cells. It is hoped that by understanding in detail how the infection begins we will discover a basis for the production of new drugs that prevent HCMV from having its often devastating effects.

Technical Summary

Human cytomegalovirus (HCMV) is a large DNA-containing virus and a member of the herpesvirus family. Infection with HCMV causes a variety of human diseases. In normal adults, infection is usually asymptomatic although the virus persists in the host in a latent state after primary infection. In immunosuppressed individuals, however, HCMV causes severe disease affecting multiple organs, due either to primary infection or to reactivation of latent virus. HCMV infection is a major problem for organ transplant recipients, often causing rejection, and in AIDS patients, resulting in widespread serious disease. Malformation of the foetus as a result of maternal infection with HCMV is the most prevalent single cause of birth defects in the developed world. Antiviral therapy with ganciclovir is reasonably effective provided the drug is administered continuously, but disease reappears upon withdrawal of treatment. Unfortunately, long term therapy is associated with toxic side effects. The pathogenesis of HCMV is poorly understood at the molecular level. In common with other herpesviruses, HCMV regulates expression of its genome in a coordinated manner. The first genes to be transcribed are classed as immediate early (IE), representing a small subset of the total viral gene content. The IE gene products include regulators of transcription which combine to ensure the expression of the remaining genes. Our research is concerned with a protein constituent of the virus particle, pp71, that stimulates IE transcription and is important in initiating the infection process that ultimately results in cell death and virus production. We aim to understand at the molecular level how pp71 activates IE gene expression. We have shown that pp71 stimulates HCMV IE transcription by disrupting a complex between two cellular proteins, Daxx and ATRX. In this way, the virus overcomes a host cell intrinsic defence against infection, thereby permitting virus replication and cell death. A detailed understanding the interaction between pp71, Daxx and ATRX will aid the development of antiviral agents that can block infection, and in addition may provide information relevant to the problem of HCMV latency. An unexpected spin-off from the work has already arisen: pp71 antagonises host responses that shut off expression of the HSV-1 genome, and this may assist in the development of new viral vectors for human gene therapy.

Publications

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Preston C (2008) Encyclopedia of Virology