1 Ophthalmology and Visual Sciences Research Centre and 2 The Charles T. Campbell Ophthalmic Microbiology Laboratory, Department of Ophthalmology, and 3 Department of Molecular Genetics and Biochemistry, University of Pittsburgh, Pittsburgh, PA, USA
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Abstract |
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Keywords: antiviral therapy , conjunctivitis , keratoconjunctivitis , HPMPC , cidofovir , animal models , drug effects
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Adenoviruses and the target diseases for antiviral development |
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Adenovirus infections have many clinical presentations in the immunocompetent individual, with the most common type of infection being subclinical. However, over half of adenovirus serotypes can cause clinical disease associated with one or multiple organs, of which the most common are the respiratory, gastrointestinal and genitourinary tracts, the liver and the eye. A thorough treatise on clinical diseases associated with adenoviruses has been recently presented elsewhere.5 For example, it is estimated that some 5% of acute respiratory illnesses in children under 5 are due to adenovirus infection, and gastrointestinal disease induced by adenovirus is considered a major contributing factor to childhood diarrhoea in underdeveloped and high population density areas. By and large, these diseases are of short duration with few long-term consequences and do not warrant the development of antivirals. Infection generally induces a strong adaptive and protective immunity that usually limits disease instigated by the same or closely related serotypes. There has been some vaccine development, and live vaccines have been used in both the USA and Canada to protect military recruits against adenovirus-induced respiratory disease. However, vaccination is not routinely carried out in the general population and the vaccine serotypes (Ad4 and Ad7) are not normally associated with epidemic keratoconjunctivitis (EKC), one of the target diseases for antiviral development. There is a low prevalence of antibody against the most common serotypes of adenovirus that cause EKC (Ad8, Ad19 and Ad37).
There are two specific clinical circumstances in which an effective adenovirus antiviral would have a considerable impact on morbidity associated with adenovirus infections. The first concerns the immunocompromised individual, where increased morbidity and mortality associated with adenovirus infections occurs, predominantly as a result of the increased severity of adenoviral infection and the inability of adaptive immunity to limit disease.6,7 Incidences of up to 10% occur in liver transplant recipients, and > 60% of immunocompromised adenovirus-infected individuals develop clinical symptoms. Disseminated adenovirus disease with multiple organ involvement is much more frequent, severe and has increased mortality in the immunocompromised.8,9 In particular, there has been an emergence of fatal disseminated adenovirus infections, with up to 21%80% mortality, in paediatric and bone marrow transplant patients.7,1012 This has dramatically framed the urgent need for an effective systemic antiviral agent.
The second circumstance in which antivirals would have an impact is in occurrences of disease of the ocular surface.3 Ocular adenovirus infections are common, although there is no accurate incidence and epidemiological data in the USA or Europe. However, adenovirus ocular infections are particularly rife in Japan, where over 1 million cases are reported to a National Epidemiological Surveillance of Infectious Agents registry. There are three clinical presentations of ocular disease: follicular conjunctivitis (FC), which is relatively mild and usually lasts for 35 days; pharyngeal conjunctival fever (PCF), which is associated with cold-like symptoms and conjunctivitis lasting 57 days; and EKC, a more serious condition involving the cornea and conjunctiva, which may have long-term consequences on visual acuity. EKC is accompanied with some or all of several distressing symptoms (photophobia, moderate to severe irritation, foreign body sensation, increased tearing, lid swelling and sometimes conjunctival haemorrhages) and usually spreads to the second eye in a milder form. The acute phase involving viral replication usually lasts up to 2 weeks. However, following the acute phase of EKC, there is often an immune T cell mediated infiltration of the corneal stroma, leading to the formation of multiple small, white dots (sub-epithelial infiltrates) that can cause disturbances in vision (e.g. decreased visual acuity, photophobia) for periods of months and sometimes years. The majority of cases of EKC are believed to be caused by select species D viruses, including Ad8, Ad19 and Ad37, whereas FC and PCF are most commonly associated with serotypes Ad3, Ad4 and Ad7. However, over half of 51 adenovirus serotypes have been associated with ocular diseases. In an environment with a lack of effective antivirals, treatment is currently limited to symptomatic therapy and physician-recommended epidemiological control measures to reduce transmission; or to topical corticosteroid treatment to alleviate the immune infiltration.3 The latter can be difficult to manage by the physician, owing to rebound effects of these infiltrates following steroid withdrawal, and the adverse consequences of chronic topical steroid therapy (glaucoma, cataracts and microbial superinfection).
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Development of animal models for antiviral testing |
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The promise and problems of cidofovir |
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In the rabbit model, cidofovir successfully and significantly reduced adenovirus titres, even with infrequent topical dosing, in both therapeutic and prophylactic applications.18,2225 The effectiveness of cidofovir was presumably a result of rapid corneal penetration, coupled with a documented prolonged intracellular half life.19,26 Interestingly, cidofovir demonstrated high efficacy against herpes simplex virus type 1 (HSV-1) replication and HSV-1-induced keratitis in the rabbit model, with dosing regimens of much lower frequency than current topical antiherpetic therapy.27 The success of cidofovir in numerous studies using the rabbit model ultimately resulted in a large, multicentre, randomized and controlled clinical trial carried out in the USA to evaluate cidofovir against human adenovirus ocular infections. Results from the trial (unpublished results) indicated that there was significant efficacy of cidofovir in the rapid clearance of adenovirus in the presenting eye, in the protection of the fellow eye from infection and in the reduction in the number of sub-epithelial infiltrates. However, recent off-label usage in Europe and Hawaii of higher doses of topical cidofovir for > 1 week was associated with rare cases of lachrymal canalicular blockade. Interestingly, such blockade was suggested from the rabbit model studies,22 but was not observed in pre-clinical, non-human primate studies. Clinical concerns about a narrow efficacy/toxicity ratio and marketing considerations led Bausch & Lomb Pharmaceuticals to abandon cidofovir development in the USA. The laboratory isolation of adenoviruses resistant to cidofovir with apparently normal pathogenesis in animal models20,28 also added to concerns regarding the possible emergence of clinical resistance following widespread usage. Despite the failure of the USA trials, several small clinical trials in Europe continue to evaluate cidofovir for the treatment of human adenovirus ocular infections.29,30
Whereas topical cidofovir has not undergone further clinical development, there has been broader parenteral application beyond its approved use for treatment of hCMV in AIDS patients to control adenoviral disease in life-threatening conditions. Several case reports, as well as some larger retrospective studies, indicate that cidofovir appears to be at least partially effective in limiting systemic adenoviral complications and reducing blood adenovirus DNA loads in adult and paediatric bone marrow transplant patients.3136 The high morbidity and mortality associated with systemic adenoviral infections in this patient population appear to warrant the risks, side effects and nephrotoxicity of cidofovir, which are well documented from its clinical use in the treatment of severe hCMV disease in AIDS patients.21,37
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Ribavirin |
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Additional compounds with potential for development |
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Other nucleosides with anti-adenoviral activity include the antiretroviral nucleoside analogue 2',3'-dideoxycytidine (ddC, also known as zalcitabine), which has efficacy against multiple adenovirus serotypes in vitro47,51, as well as against Ad2 in the mouse pneumonia model.15 The HIV-effective antiviral 6-azacytidine also appears to inhibit adenovirus replication in vitro53,54 and is effective against multiple adenovirus serotypes, with IC50 concentrations from 3.548.7 µg/mL.47
Several non-nucleoside agents have antiviral activity to adenovirus, including the sulfated sialyl lipid NMSO3.55,56 The mechanism of antiviral activity of NMSO3 appears to be the inhibition of virus adsorption. A second agent is the endogenous microbicide N-chlorotaurine, which is found in the supernatant of stimulated granulocytes. Its mechanism is thought to be through the oxidization of thiols and amines, and its antimicrobial activity is immediate following contact. This has demonstrated antimicrobial activity against adenoviruses as well as bacteria fungi and HSV-1.57,58 N-chlorotaurine was safe when administered topically to eyes of both rabbits and humans and in guinea-pig ears,59,60 and demonstrated efficacy compared with gentamicin in the improvement of clinical signs of viral conjunctivitis in a small clinical trial performed in Austria.61 This antiseptic-like agent may have much broader applications for conjunctivitis as it may also be effective against other viral and bacterial causes.
The non-nucleoside doxovir (also known as CTC-96), represents a new class of antiviral agent, the cobalt chelates, with activity against adenoviruses. Although incompletely characterized, the mechanism of action appears to be related to strong binding to histidine and is an imidazole derivative. In the Ad5 rabbit replication model, doxovir at 50 µg/mL eliminated virus by day 10 compared with day 21 in placebo-treated controls, and resolution of clinical conjunctivitis was fastest in the doxovir 50 µg/mL treatment group, compared with lower doxovir concentrations and placebo-treated controls.62 The agent had activity against several herpesviruses, including HSV-1 and-2, hCMV, EpsteinBarr virus, varicella-zoster virus and human herpesvirus 6 (HHV-6). Topical doxovir was as effective as Viroptic (trifluridine) in diminishing HSV-1-induced corneal disease and ocular surface titres of HSV-1 in the rabbit keratitis model.63 Doxovir may target a maturational protease in HSV-1, which is required late in the replication cycle. Its activity against both adenovirus and herpesviruses increases its value as a potential ocular antiviral.
A number of compounds have been noted to have anti-adenoviral activity in vitro, but most remain to be evaluated in animal models. These include traditional plant-derived compounds,64
plant green tea catechins,65
cycloferon,66
lactoferrin,67
heterocyclic Schiff bases of aminohydroxyguanidine tosylate,68,69
a topoisomerase inhibitor,70
and papain and protease inhibitors.71,72
Furthermore, peptidomimetic integrin-binding antagonists block adenoviruses by interfering with receptor binding.73
Finally, it has been noted that human -defensin peptides are effective against adenoviruses in vitro.74
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Future issues in the development of adenovirus antivirals |
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Breadth of serotype efficacy
It is clear that optimal antivirals to adenoviruses must have broad serotype specificity. Multiple serotypes can cause similar diseases, despite some often extensive primary protein sequence and structural divergence. By and large, serotyping of the causative adenovirus is not routinely carried out in a diagnostic setting, and so compounds with wider serotype breadth offer distinct advantages over those with narrower specificity. A topical antiviral for ocular disease would hopefully target at least the most common pathogenic serotypes that cause EKC (Group D Ad8, Ad19, Ad37), PCF and FC (Group B Ad3, Ad7; Group E Ad4; and Group C Ad1, Ad2, Ad5, Ad6). Targeting of respiratory diseases would also require an extensive serotype breadth to be effective.
Antiviral targeting
The ideal antiviral would target a virus-specific process that does not have homologous processes in the host. Whereas adenoviruses encode their own DNA polymerases that are structurally divergent from host polymerases, both utilize the same nucleotide substrates, and the basic replication machinery is similar. As adenoviruses lack nucleotide metabolism enzymes found in herpesviruses, the nucleoside activation principle using nucleotide pool modifying enzymes cannot be applied to adenoviruses and antiviral effectiveness must rely on preferential activity on the viral polymerase over the host's polymerases. However, there are multiple, highly specific virus processes for which antiviral strategies could be developed, including attachment, uncoating, virion assembly and targeting of key viral protein:protein interactions. High throughput screens to identify lead compounds acting on such processes for adenoviruses largely remain to be developed. However, it is encouraging that several antiherpesvirus antiviral strategies have recently been developed that target key protein:protein interactions.75
Clinical trial challenges
The design and execution of large, controlled, clinical trials required prior to government approval for any antiviral has some critical hurdles to overcome, particularly with regard to adenovirus ocular diseases. Patient capture for enrolment may be a problem, as the milder ocular diseasesPCF and FCare seasonal, self-limited, of short duration and may not be seen or referred to a physician. EKC occurs in sporadic epidemics in the western world, and as such, patient enrolment will require multiple centres in geographically diverse sites in the USA or Europe to capture sufficient patients for EKC trials. An alternative would be to evaluate such antiviral candidates in clinical trials in Asia (Japan, China, Korea), where adenoviral infections are endemic. Accurate diagnosis may also be a key issue, as many adenoviral ocular and respiratory infections mimic clinical symptoms caused by many infectious and non-infectious agents. Rapid diagnostic serotyping may also be important if an antiviral with limited serotype breadth of efficacy is to be evaluated in clinical trials. A successful clinical trial must address the logistics and costs of rapid laboratory diagnosis (real-time PCR, enzyme immunoassay, culture) for timely enrolment. Our experience from the cidofovir trials indicated difficulty in demonstrating antiviral efficacy in cases where correct diagnosis was delayed.
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Conclusion |
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Acknowledgements |
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References |
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