Antiviral treatment efficiently inhibits chikungunya virus infection in the joints of mice during the acute but not during the chronic phase of the infection

Abstract

Favipiravir (T-705) is a broad spectrum antiviral which has been approved in Japan for the treatment of severe influenza virus infections. We reported earlier that favipiravir inhibits the in vitro replication of CHIKV and protects against disease progression in CHIKV-infected immunodeficient mice. We here explored whether favipiravir is also able to inhibit CHIKV replication in the joints of mice either when treatment is initiated during the acute or during the chronic phase of the infection. To this end, C57BL/6J mice were infected with CHIKV in the left hind footpad and treatment with favipiravir (300 mg/kg/day, orally) was either given from day 0 to day 3 post-infection (p.i.) or from day 49 to day 55 p.i. In the untreated mice, viral RNA was still detectable in the joints up to 98 days p.i., yet no infectious viral particles were observed in these tissues. The 4 days treatment during the acute phase of the infection resulted in complete inhibition of systemic viral spread. As a consequence, no viral RNA was detected in the non-inoculated feet in contrast to the situation in the untreated control mice. When treatment was initiated at day 49 p.i., no significant reduction in viral RNA levels in joints were noted as compared to the untreated control. Interestingly, when attempting to amplify by RT-PCR material corresponding to virus genome from the chronic phase samples, some parts of the genome, such as the viral polymerase gene could not be amplified. Collectively, these results suggest that the viral RNA detected in the joints during the chronic phase is likely defective, which also explains the lack of effect of a viral replication inhibitor.

Keywords: CHIKV; Favipiravir; Joints; Mice; Persistence.