Genetic Flexibility of the NKNK Motif in HIV-1 Integrases Allows Its Involvement in Multiple Functions During Infection

Abstract

Generating chimerical integrases between isolates of the HIV-1 group responsible for the AIDS pandemic (group M) and of the minor group O, we identify a new functional motif, in the C-terminal domain of integrases M, constituted of two lysines and two asparagines (NKNK). Removing these residues abolishes catalysis in vitro and the generation of proviral DNA in tissue culture. A decrease of reverse transcription and nuclear import of reverse transcription products is also observed. Remarkably, the motif shows a potential genetic flexibility with respect to integration. Indeed, despite its strict conservation in vivo, the positions of the residues in the motif can be permutated retaining in most cases the ability to generate proviral DNA. Reverse transcription is instead optimal exclusively with the canonical NKNK motif. The versatility of this region regarding integration could therefore have provided a major asset for this enzyme to acquire additional functions in the infectious cycle.