Drivers of within-host genetic diversity in acute infections of viruses

Author summary The few days or weeks following infection with a virus, termed acute infection, are critical for virus establishment. Here we sought to characterize what leads to differences in the genetic diversity of different viruses sampled during acute infection. We performed ultra-deep sequencing of hundreds to thousands viral genomes from forty-three samples spanning three pathogenic human viruses: HIV, RSV and CMV. We found major differences in the genetic diversity of these different viruses, and in different patients infected with the same virus. We investigated the factors responsible for these differences. We found that the DNA virus CMV was less diverse, most likely since it has a lower mutation rate than the RNA viruses HIV and RSV. We also found that the samples with the highest genetic diversity, which included one CMV sample and two HIV samples, bore evidence for multiple genotype infection. In other words, patients from whom these sample were taken were infected with two different strains of the virus. Finally, we also found evidence that viral genomes of HIV, and in particular RSV, are edited by the innate immune system of the host, leading to the presence of defective virus genomes. Genetic diversity is the fuel of evolution and facilitates adaptation to novel environments. However, our understanding of what drives differences in the genetic diversity during the early stages of viral infection is somewhat limited. Here, we use ultra-deep sequencing to interrogate 43 clinical samples taken from early infections of the human-infecting viruses HIV, RSV and CMV. Hundreds to thousands of virus templates were sequenced per sample, allowing us to reveal dramatic differences in within-host genetic diversity among virus populations. We found that increased diversity was mostly driven by presence of multiple divergent genotypes in HIV and CMV samples, which we suggest reflect multiple transmitted/founder viruses. Conversely, we detected an abundance of low frequency hyper-edited genomes in RSV samples, presumably reflecting defective virus genomes (DVGs). We suggest that RSV is characterized by higher levels of cellular co-infection, which allow for complementation and hence elevated levels of DVGs.