The mechanisms of recombination in human immunodeficiency virus

Abstract

The importance of recombination in retroviral evolution has been acknowledged for several decades. After the identification of HIV as the etiological agent of AIDS, it was suspected that recombination could also play a central role in the evolution of this virus. However, only recently extensive epidemiological studies of HIV infections worldwide have provided an estimate for the occurrence of recombination in vivo, unveiling recombination frequencies that dwarf those initially expected. Nowadays, recombination is regarded as an integral part of the infectious cycle of this retrovirus, demonstrating its major role in HIV evolution. Retroviral recombination can occur when two genetically divergent genomic RNA molecules are present in the same viral particle, and arises during reverse transcription. Here we focuse on the mechanisms that have been proposed to account for the occurrence of recombination in retroviruses, from the strand displacement model, according to which recombination occurs during second DNA strand synthesis; to the description of the factors responsible for copy-choice recombination during first DNA strand synthesis, such as the presence of breaks, pause sites, or secondary structures in the genomic RNA. Most of these models have been supported by experimental data obtained from in vitro reconstituted systems or from cell infection studies using academic model sequences. The situation in vivo must be more complex, since several factors come into play when recombination involves relatively distant isolates, as in the case of inter-subtype recombination. At present, it is clear that further studies are needed in order to evaluate whether a prevailing mechanism exists for in vivo recombination, and will also be essential for understanding how the underlying mechanisms of recombination contribute to the evolution of HIV.