<jats:title>Abstract</jats:title> <jats:p>Pathogen-driven selection and past interbreeding with archaic human lineages have resulted in differences in HLA-allele frequencies between modern human populations. Whether or not this variation affects pathogen subtype diversification is unknown. Here we show a strong positive correlation between ethnic diversity in African countries and both HIV-1 p24gag and subtype diversity. We demonstrate that ethnic HLA-allele differences between populations has influenced HIV-1 subtype diversification as the virus adapted to escape common antiviral immune responses. The evolution of HIV subtype B (HIV-B), which does not appear to be indigenous to Africa, is strongly affected by immune responses associated with Eurasian HLA variants acquired through adaptive introgression from Neanderthals and Denisovans. Furthermore, we show that the increasing and disproportionate number of HIV-infections among African Americans in the United States drive HIV-B evolution towards an Africa-centric HIV-1 state. Similar adaptation of other pathogens to HLA variants common in affected populations is likely.</jats:p>