Human cytomegalovirus (HCMV) is a human herpesvirus which causes little or no disease in the immunocompetent. However, in immunocompromised individuals, neonates, or patients on immune suppressive therapies, HCMV can cause significant morbidity and mortality in some patient groups. As with all herpesviruses, HCMV has two life cycle phases: a productive phase, where new virions are produced and a latent phase where there is a restricted gene transcription profile and no new virion production. Currently available antivirals target the productive phase of HCMV infection and, although these have greatly decreased the severity of HCMV-induced disease in immunocompromised or immunosuppressed individuals, they often have associated toxicities, routinely result in selection of drug resistant viral mutants, and, importantly, they do not target cells latently infected with virus. Thus, there is a real need to derive novel antiviral therapies which, not least, are also able to target latent infection. In this paper, we describe recent work which has begun to analyse changes in the cell associated with latent infection and the possibility that these latency-associated changes in cell phenotype could be targeted by novel chemo- or immunotherapeutic strategies in order to diminish, or even clear, latent infection at least in some specific clinical settings. 1. Review of the Literature and the Development of Tissue Culture Latency Models 1.1. Epidemiology and Clinical Aspects Human cytomegalovirus (HCMV) is a pathogen that can cause significant morbidity and mortality, particularly in the immunocompromised host [1–10]. For instance, HCMV disease is regularly seen after infection of individuals with a suppressed immune system, such as transplant patients or those suffering from AIDS. In such individuals, HCMV-associated pathology is observed in a range of tissues and can lead to an array of diseases including retinitis and pneumonitis as well as bowel and heart disease ([1, 3, 4, 10] and see Figure 1). Similarly, infection in utero, in the developing immunonaive foetus, can result in mental retardation, deafness, and blindness [5–9] which impact substantially QUALYS (quality adjusted life years) measurements and, for these reasons, HCMV has been named as a high vaccine priority [11]. Figure 1: HCMV-induced disease pathology. HCMV causes disease in individuals where the immune system is compromised. Mental retardation, deafness, and blindness can occur following in utero primary infection [ 5– 8]. Retinitis occurs following primary infection and reactivation in AIDS
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