Experimental evolution of a mouse-specific retrovirus in various host genotypes reveal increases in fitness and virulence by 50- and 20-fold respectively. The virus adapts to specific host genotypes as indicated by its’ reduced ability to infect other host genotypes, including those that differ only at histocompatibility loci. Three round serial passages where the host genotype is alternated once, dramatically reduces viral fitness and virulence. Full genome sequencing of these evolved viral lines reveal surprising results where no mutations have become fixed despite strong selection operating over 240 generations.