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, 85 (7), 3677-82

Differential Sensitivities of Retroviruses to Integrase Strand Transfer Inhibitors

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Differential Sensitivities of Retroviruses to Integrase Strand Transfer Inhibitors

Yasuhiro Koh et al. J Virol.

Abstract

Integrase inhibitors are emerging anti-human immunodeficiency virus (HIV) drugs, and multiple retroviruses and transposable elements were evaluated here for susceptibilities to raltegravir (RAL) and elvitegravir (EVG). All viruses, including primate and nonprimate lentiviruses, a Betaretrovirus, a Gammaretrovirus, 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 intracisternal A-particle retrotransposition but were inactive against Sleeping Beauty transposition and long interspersed nucleotide element 1 (LINE-1) retrotransposition.

Figures

FIG. 1.
FIG. 1.
IN mutant virus infectivities. (A) Normalized levels of HIV-1 IN mutant infectivities compared to that of the WT, which was set at 100%. (B) Same as panel A, except that RSV was studied.
FIG. 2.
FIG. 2.
IN sequence alignment and contribution of potential amino acid residues to resistance to INSTIs. Green indicates residues that when changed can confer resistance to RAL and/or EVG; magenta marks residues known to confer resistance when present at the analogous HIV-1 position; gray indicates residues with unknown effects on potential HIV-1 resistance; red indicates active-site residues; and blue highlights a conserved DNA binding residue (15). Numbers above the alignment indicate HIV-1 amino acid positions; those to the left and right mark positions in the respective IN or transposase protein sequences. Underlining marks the positions of secondary structural elements for HIV-1 (19), SIV (4), RSV (52), and PFV (10) INs and the positions of SB elements from a structure-based alignment with the related Mos1 transposase (37).

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