Although the host immune response certainly plays a significant role in the selection of recombinant variants in vivo [13] , the similarities between the natural and experimental breakpoint distributions suggest that the forces responsible for the selection of recombinants in vivo only have limited impact on inter-subtype breakpoint patterns in env. This is most likely due to a combination of factors including mainly the complex epistatic interactions within env, the high density of fitness-determining loci within this gene, and the biochemical mechanism of recombination, which collectively constrain the fixation of genetic variability introduced by recombination. Negative fitness effects associated with recombination in env, however, should decrease with decreasing parental genetic distances [3, 6, 39] and therefore, in the context of intra-subtype recombination, the selective constraints on recombinants should be more relaxed than we have found them to be here.