Human Cytomegalovirus Latency: Targeting Differences in the Latently Infected Cell with a View to Clearing Latent Infection

Emma Poole,John Sinclair,Mark Wills

doi:10.1155/2014/313761

Abstract

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.

Highlights

Others, a number of models of experimental latency have been established for in vitro analysis of Human cytomegalovirus (HCMV) latency and reactivation. These include primary myeloid progenitors such as granulocyte macrophage progenitors (GMPs) or CD34+ haematopoietic progenitor cells as well as CD14+ monocytes [37, 49, 55,56,57,58,59]; all can be cultured and experimentally infected to establish a latent infection which can be reactivated by differentiation signals—which very much reflects models of natural latency
Whilst our own work using established experimental latency protocols has contributed to such studies on latencyassociated viral gene expression [49, 71, 72], we have analysed a number of changes in cellular gene expression during latent infection [45, 78]
Studies on the latency-associated secretome from experimental latency using primary CD34+ cells have identified significant increases in a number of cellular proteins secreted during latent infection [78]

Summary

Introduction

These include primary myeloid progenitors such as granulocyte macrophage progenitors (GMPs) or CD34+ haematopoietic progenitor cells as well as CD14+ monocytes [37, 49, 55,56,57,58,59]; all can be cultured and experimentally infected to establish a latent infection which can be reactivated by differentiation signals—which very much reflects models of natural latency. Whilst our own work using established experimental latency protocols has contributed to such studies on latencyassociated viral gene expression [49, 71, 72], we have analysed a number of changes in cellular gene expression during latent infection [45, 78].

Results

Conclusion