NOTES Differential Sensitivities of Retroviruses to Integrase Strand Transfer Inhibitors

Integrase inhibitors are emerging anti-human immunodeficiency virus (HIV) drugs, and multiple retrovi-ruses and transposable elements were evaluated here for susceptibilities to raltegravir (RAL) and elvitegravir (EVG). All viruses, including primate and nonprimate lentiviruses, a Betaretrovirus, aGammaretrovirus, and the Alpharetrovirus Rous sarcoma virus (RSV), were susceptible to inhibition by RAL. EVG potently inhibited all lentiviruses and intermediately inhibited Betaretrovirus and Gammaretrovirus infections yet was basically ineffective against RSV. Substitutions based on HIV type 1 (HIV-1) resistance changes revealed that integrase residue Ser150 contributed significantly to the resistance of RSV. The drugs intermediately inhibited intra-cisternal A-particle retrotransposition but were inactive against Sleeping Beauty transposition and long interspersed nucleotide element 1 (LINE-1) retrotransposition. Reverse transcription of retroviral RNA yields linear viral DNA (vDNA) containing a copy of the long terminal repeat (LTR) at each end. Integrase (IN) is an essential retroviral enzyme that catalyzes two reactions to insert the vDNA into cellular chromosomal DNA. IN prepares the LTR ends by hydrolyzing phosphodiester bonds adjacent to invariant C