The interferon response is a potent antiviral defense mechanism, but its effectiveness in host protection depends on its timing relative to viral replication. Here, we report viral replication and host response kinetics at the start of SARS-CoV-2 infection. Using longitudinal patient nasopharyngeal samples and airway epithelial organoids, we found that SARS-CoV-2 initially replicated exponentially with a doubling time of ~6hr, and induced interferon stimulated genes (ISGs) with delayed kinetics relative to viral replication. Prior exposure to rhinovirus increased ISG levels at the start of SARS-CoV-2 infection and completely blocked SARS-CoV-2 replication. Conversely, inhibiting ISG induction abrogated interference by rhinovirus and increased SARS-CoV-2 replication rate. These results demonstrate the importance of initial interferon-mediated defenses in determining the extent to which SARS-CoV-2 can replicate and indicate that biological variables that alter the airway interferon response could profoundly impact SARS-CoV-2 infection and transmission.

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