Development of ganciclovir as an anti-human cytomegalovirus drug: historical perspectives and future prospects

Human cytomegalovirus (HCMV) infection is widespread within the global human population and is a major cause of human morbidity and mortality. As yet, there is no widely available anti-HCMV vaccine strategy. Therefore, treatment of HCMV disease relies on anti-HCMV drugs, principally the nucleoside analogue pro-drug ganciclovir (GCV). While it is over 40 years since the discovery of GCV as an anti-HCMV compound, the use of GCV in humans is still developing, for example in the treatment of congenital HCMV infection. Here, we provide an overview of often overlooked virological laboratory studies underpinning GCV development. We highlight long-standing, but rarely examined, data on adverse effects that is the basis for caution in using GCV during pregnancy or in children. This includes discussion of recent, contrasting data, suggesting that GCV can be further developed to treat congenital HCMV infection. To better understand how adverse effects may come about, we also review the viral and cellular factors required for GCV function in HCMV-infected and uninfected cells. This leads to a discussion of how adverse effects of GCV may or may not be avoided and future directions involving the use of GCV. Overall, these topics highlight how much molecular information remains to be understood about one of the oldest and most widely used anti-HCMV drugs in humans.