Mechanistic Features of Recombination in HIV

The importance of recombination in retroviral evolution has been acknowledged for several decades.Consequently, after the identification of HIV as the etiological agent of AIDS, it was suspected thatrecombination could also play a central role in the evolution of this virus. However, only recently,extensive epidemiologic studies of HIV infections worldwide have provided an estimate for the occurrenceof recombination in vivo, unveiling recombination frequencies that dwarf those initiallyexpected. Nowadays, recombination is regarded as an integral part of the infectious cycle of thisretrovirus, which impacts on diagnosis and treatment of infections, especially when genetically distantviruses have been at the origin of the recombinant forms. Retroviral recombination is observedwhen two genetically divergent genomic RNA molecules are present in the same viral particle, andarises during the reverse transcription step. This review focuses on the mechanisms that have beenproposed to account for the occurrence of recombination in retroviruses, from the strand displacementmodel, according to which recombination occurs during second DNA strand synthesis; to thedescription 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. Mostof these models have been supported by experimental data obtained from in vitro reconstitutedsystems or from cell infection studies using academic model sequences. The situation in vivo isexpected to be more complex, since several factors come into play when recombination involvesrelatively distant isolates, as in the case of inter-subtype recombination. At present, it is clear thatfurther studies are needed in order to evaluate whether a prevailing mechanism exists for in vivorecombination, and these studies will also be essential for understanding how the underlying mechanismsof recombination contribute to the evolution of HIV.