Mutations in chikungunya virus nsP4 decrease viral fitness and sensitivity to the broad-spectrum antiviral...

Area of Science:

• Virology
• Drug Discovery
• Infectious Diseases

Background:

• Chikungunya virus (CHIKV) causes widespread human infections, with no current approved antiviral treatments.
• The ribonucleoside analog 4 -fluorouridine (4 -FlU) effectively inhibits CHIKV replication by targeting the viral RNA-dependent RNA polymerase (nsP4).
• Previous studies demonstrated 4 -FlU's efficacy in reducing viral loads and disease signs in mouse models.

Purpose of the Study:

• To assess the potential of 4 -FlU as a Chikungunya virus antiviral.
• To identify and characterize CHIKV variants with reduced sensitivity to 4 -FlU.

Main Methods:

• Selection of CHIKV variants resistant to 4 -FlU.
• Identification of mutations in viral proteins nsP2 and nsP4.
• Assessment of 4 -FlU sensitivity, viral fitness (in vitro and in vivo), and nsP4 fidelity.
• Pathogenesis studies in mouse models using identified CHIKV variants.

Main Results:

• Two pairs of mutations in nsP2 and nsP4 conferred decreased 4 -FlU sensitivity, with nsP4 mutations Q192L and C483Y being primarily responsible.
• Resistant variants remained susceptible to higher concentrations of 4 -FlU.
• Identified mutations did not affect nsP4 fidelity or confer a viral fitness advantage.
• The nsP4-C483Y variant exhibited similar pathogenesis to wild-type CHIKV, while the nsP4-Q192L variant was attenuated in mice.

Conclusions:

• The identified resistance mutations do not fully abrogate 4 -FlU's antiviral activity.
• The study supports the potential of 4 -FlU as a viable antiviral therapeutic for Chikungunya virus infections.
• Further investigation into 4 -FlU's efficacy and resistance profile is warranted.