Amiodarone increases positive-strand RNA virus replication in vitro: implications for its use in patients with viral infections

Sir,

Amiodarone, a cationic amphiphilic drug, is a widely used antiarrhythmic agent endowed with anti-infective properties.¹ Recently, at concentrations close to serum levels reached in patients, it has been shown to inhibit Ebola virus infection in vitro by interfering with the viral entry step.^2,3 Amiodarone accumulates in cell membranes and acidic organelles, inducing changes that recapitulate the phenotype observed in Niemann–Pick type C disease.¹ Interestingly, the inhibitory effect of amiodarone on Ebola virus infection appears to correlate with its ability to induce a Niemann–Pick type C-like phenotype.³ To counteract the 2014 outbreak of Ebola virus disease (EVD) in West Africa, the WHO Ebola Response Roadmap focused on ‘accelerated development and clinical evaluation of promising experimental interventions’. In this context, several clinical trials were announced by the end of 2014, among which one aimed to investigate the effect of amiodarone in patients with EVD.⁴ To clarify amiodarone antiviral properties, we studied its effect on infections due to Crimean–Congo haemorrhagic fever virus, an enveloped negative-stranded RNA virus, dengue virus serotype 4 (DENV4), an enveloped positive-stranded RNA virus and enterovirus 8362 (EV8362), a naked positive-stranded RNA virus. The effect on viral release was investigated using the same experimental setting previously employed for Ebola virus.³ Vero cells, pretreated for 16 h with 5 and 10 μM amiodarone, were infected with the different viruses at the appropriate moi, cultured in the presence of amiodarone for 24–48 h and viral progeny was estimated by viral titration.^3–5 As reported in Table 1, in the case of Crimean–Congo haemorrhagic fever virus we observed a mild effect on viral titre, thus supporting the specificity of amiodarone activity towards Ebola virus. On the other hand, DENV4 viral progeny was slightly increased by amiodarone treatment, independent of the concentration employed. However, the value was not statistically significant. By contrast, more than a 1 log increase in infectious particle production was detected in the case of EV8362. The effect on DENV4 and EV8362 was also present in the absence of amiodarone pretreatment (data not shown). It has been demonstrated that autophagy modulates the replication of RNA viruses⁶ and enterovirus 71-induced autophagy increases viral replication and pathogenesis.⁷ Thus, the increased replication of EV8362 could be explained by the amiodarone-induced autophagy.^1,8 Although additional studies in vitro and in vivo on the effects of amiodarone on enterovirus and other positive-stranded RNA viruses are required, the possibility of enterovirus coinfection in patients with EVD should be taken into account in clinical trials involving amiodarone. Furthermore, infection with enterovirus should also be considered in the vast cohort of patients treated with amiodarone for cardiac arrhythmias. Finally, it appears that cationic amphiphilic drugs, in general, should be studied for possible interference with the life cycle of clinically important positive-stranded RNA viruses.

Funding

This work was supported by University of Padova grants (ex 60% to C. S., A. C. and A. B. and Progetti di Ateneo 2008 to A. B.), EScential (Infect-ERA) and Swedish Research Council grants to A. M., and Regione Veneto grants to C. P. and G. P.

Transparency declarations

None to declare.

References