Getting to the root of HIV transmitted founder virus sequences

Determining the sequence of the transmitted founder virus, the virus that establishes infection in a new host, is critical for understanding early viral dynamics and evolution. Methods to estimate transmitted founder virus sequences using ancestral sequence reconstruction require either sequences collected early in infection or longitudinal samples that can capture the evolutionary history of the viral sequences, which can be challenging to collect. In human immunodeficiency virus infection, viral genomes are integrated into host cells which can persist, creating a proviral archive of the evolutionary history of the virus. We can potentially utilize these proviral sequences, which can be collected later during infection and while the individual is on therapy, to perform ancestral sequence reconstruction to estimate founder virus sequences. We analysed a previously described data set of 12 participants from Zambia who had human immunodeficiency virus sequences collected within months of infection and proviral sequences collected before and after suppressive therapy initiation. We investigated the accuracy of root placement and founder virus sequence reconstruction in these individuals from their proviral sequences using a variety of phylogenetic methods. We had limited success in reconstructing founder virus sequences across all ancestral sequence reconstruction and rooting methods. However, we observed lower error in founder virus sequence reconstruction with participants that had proviral sequences similar to their founder sequence. Our results highlight a need for new methods to be developed in order to effectively reconstruct founder virus sequences from proviral sequences.