The genomic sequence of packaged viral ribonucleic acid predicts mucosal HIV-1 transmission fitness.

RNA viruses are responsible for many zoonotic disease transmission events, and remain a global health challenge. To evade immune detection, RNA viruses suppress the numbers of immunostimulatory oligonucleotide motifs (INMs) present in their genomes. Although this is thought to occur in human immunodeficiency virus-1 (HIV-1), our bioinformatic analysis on well characterized clinical datasets, along with in vitro studies, demonstrate that HIV-1 is enriched for INMs within its transmitted/founder (T/F) population relative to non-transmitting variants. Importantly, our data suggests that within the host, there is an evolutionary genetic replacement of T/F viruses that otherwise exhibit high transmission fitness and low replicative fitness, with variants having low transmission fitness but high replicative fitness. These findings provide insights into HIV-1 transmission by studying within-host and between-host evolutionary dynamics, enabling us to identify a framework for HIV infection biology, with viral RNA playing a role in transmission and replication processes.