Support for the Transmission-Clearance Trade-Off Hypothesis from a Study of Zika Virus Delivered by Mosquito Bite to Mice

Evolutionary theory indicates that virus virulence is shaped by a trade-off between instantaneous rate of transmission and duration of infection. For most viruses, infection is curtailed by immune clearance, but there are few empirical tests of the transmission–clearance trade-off hypothesis. We exposed A129 mice to bites from groups of 1, 2–4, or 6–9 Aedes albopictus mosquitoes infected with Zika virus (ZIKV). We predicted that a higher number of infectious mosquito bites would deliver a higher total dose of the virus, and that increasing dose would result in earlier onset, higher magnitude, and shorter duration of viremia, as well as a more robust neutralizing antibody response. We found that increases in the number of mosquito bites delivered resulted in significantly different virus replication dynamics with higher, earlier peak titers. All mice experienced a transient weight loss following infection, but the nadir in weight loss was delayed in the mice that received the highest number of bites. Viremia persisted past the period of measurement in this study, so we did not capture its duration. However, the association at the level of the individual mouse between the estimated virus dose delivered and neutralizing antibody titer was remarkably strong, supporting the transmission–clearance trade-off hypothesis.