Cytomegalovirus antivirals and development of improved animal models

Abstract

Introduction Cytomegalovirus (CMV) is a ubiquitous pathogen that establishes a life long asymptomatic infection in healthy individuals. Infection of immunesuppressed individuals causes serious illness. Transplant and AIDS patients are highly susceptible to CMV leading to life threatening end organ disease. Another vulnerable population is the developing fetus in utero, where congenital infection can result in surviving newborns with long term developmental problems. There is no vaccine licensed for CMV and current antivirals suffer from complications associated with prolonged treatment. These include drug toxicity and emergence of resistant strains. There is an obvious need for new antivirals. Candidate intervention strategies are tested in controlled pre-clinical animal models but species specificity of HCMV precludes the direct study of the virus in an animal model. Areas covered This review explores the current status of CMV antivirals and development of new drugs. This includes the use of animal models and the development of new improved models such as humanized animal CMV and bioluminescent imaging of virus in animals in real time. Expert Opinion Various new CMV antivirals are in development, some with greater spectrum of activity against other viruses. Although the greatest need is in the setting of transplant patients there remains an unmet need for a safe antiviral strategy against congenital CMV. This is especially important since an effective CMV vaccine remains an elusive goal. In this capacity greater emphasis should be placed on suitable pre-clinical animal models and greater collaboration between industry and academia.

A Novel Non-Replication-Competent Cytomegalovirus Capsid Mutant Vaccine Strategy Is Effective in Reducing Congenital Infection

“…Virus infection in a healthy host is normally asymptomatic but leads to a lifelong infection. In contrast, infection of an immunocompromised host (AIDS and transplant patients) or virus reactivation because of an impaired immune system can have severe consequences of morbidity and mortality, but established antiviral therapy can potentially reduce the impact of the disease in these patients (1). Another important aspect of cytomegalovirus disease is congenital infection, where the virus crosses the placenta and infects the fetus in utero.…”

“…This occurs in approximately 2% of live births in the United States and can lead to serious symptomatic disease, including impaired vision, mental retardation, and sensorineural hearing loss (SNHL) in newborns (2)(3)(4)(5)(6). Established antiviral therapy cannot be used because of possible teratogenic and toxic side effects associated with transmission of the drugs to the fetus in utero (1). However, long-term (6-month) valganciclovir antiviral therapy is now recommended for infants with central nervous system (CNS) involvement to improve SNHL and development outcome (7).…”

“…Importantly, guinea pig CMV (GPCMV) congenital infection causes disease in the fetus and in newborn pups similar to that found in humans, including SNHL (21)(22)(23). Consequently, the guinea pig model is well suited for testing of intervention strategies aimed at preventing congenital CMV infection (1,24,25).…”

Animal models of human cytomegalovirus congenital infection

“…By comparison, GPCMV model has proved a highly valuable model to evaluate the action of hexadecyloxypropylcidofovir (brincidofovir or CMX001) in the reduction of foetal morbidity, virus load and the manifestation of SNHL 8 . Although GPCMV is resistant to ganciclovir, the generation of GPCMV/HCMV UL97 chimaeric viruses will enable future antiviral testing of ganciclovir in vivo 9 . Poor placental transmission by MCMV precludes the evaluation of antivirals on foetal infection.…”

“…Several GPCMV vaccines (live attenuated, subunit and DNA) administered before conception, have been evaluated 5,11 . Whilst sterilising immunity to any vaccination program has not been demonstrated, Cost is high for vaccine and drug studies Similar SNHL sequelae 7 Proven model for drug efficacy 6,8,9 Proven model for vaccine immunogenicity and efficacy 5,10,11 Highly refined model with respect to virus dose, timing of infection, end organ disease 9 Mouse MCMV 230 kb Good newborn infection model 12,13 Poor transplacental transmission 6 Excellent knowledge of virus-host interactions 14 Not suited for vaccine/drug efficacy studies targeted at preventing congenital infection…”