Molecular mechanisms of recombination restriction in the envelope gene of the human immunodeficiency virus

Author Summary Recombination allows mixing portions of genomes of different origins, generating chimeric genes and genomes. With respect to the random generation of new mutations, it can lead to the simultaneous insertion of several substitutions, introducing more drastic changes in the genome. Furthermore, recombination is expected to yield a higher proportion of functional products since it combines variants that already exist in the population and that are therefore compatible with the survival of the organism. However, when recombination involves genetically distant strains, it can be constrained by the necessity to retain the functionality of the resulting products. In pathogens, which are subjected to strong selective pressures, recombination is particularly important, and several viruses, such as the human immunodeficiency virus (HIV), readily recombine. Here, we demonstrate the existence of preferential regions for recombination in the HIV-1 envelope gene when crossing sequences representative of strains observed to recombine in vivo. Furthermore, some recombinants give a decreased proportion of functional products. When considering these factors, one can retrace the history of most natural HIV recombinants. Recombination in HIV appears not so unpredictable, therefore, and the existence of recombinants that frequently generate nonfunctional products highlights previously unappreciated limits of the genetic flexibility of HIV.