The host’s anti-viral immune response is a major predictor of infection outcome. This anti-viral response is, in part, governed by a set of interconnected highly variable receptor-ligand pairs that are formed at both the germline and somatic level. The variation exhibited by these host molecules reflects the selection pressure likely exerted by pathogens through thousands of generations. However, highly mutable RNA viruses can evade these host immune responses, and such viral variations (adaptations) are a major impediment to long-lasting and effective vaccines. Understanding the complexity of the host-viral interaction is critical to immunogen design. We have utilised high-resolution genetic and cellular approaches on samples from rare cohorts of HIV-infected individuals and subjects that have been exposed to multiple influenza vaccines to determine how variation in the host and the virus can impact their interaction at the single cell level. Genetic data from thousands of viral strains, host genotypes and single cell transcriptomes highlight the multiple layers of our anti-viral immune response but also the various adaptation mechanisms utilised by viruses to enable them to continue to be global health issues.