Title: Mutations in human immunodeficiency virus type 1 integrase confer resistance to the naphthyridine L-870,810 and cross-resistance to the clinical trial drug GS-9137
Authors: Hombrouck, Anneleen
Voet, Arnout
Van Remoortel, Barbara
Desadeleer, Christel
De Maeyer, Marc
Debyser, Zeger ×
Witvrouw, Myriam #
Issue Date: Jun-2008
Publisher: American Society for Microbiology (ASM)
Series Title: Antimicrobial Agents and Chemotherapy vol:52 issue:6 pages:2069-2078
Abstract: To gain further insight into the understanding of the antiviral resistance patterns and mechanisms of the integrase strand transfer inhibitor L-870,810, the prototypical naphthyridine analogue, we passaged the human immunodeficiency virus type 1 strain HIV-1(IIIB) in cell culture in the presence of increasing concentrations of L-870,810 (IIIB/L-870,810). The mutations L74M, E92Q, and S230N were successively selected in the integrase. The L74M and E92Q mutations have both been associated in the past with resistance against the diketo acid (DKA) analogues L-708,906 and S-1360 and the clinical trial drugs MK-0518 and GS-9137. After 20, 40, and 60 passages in the presence of L-870,810, IIIB/L-870,810 displayed 22-, 34-, and 110-fold reduced susceptibility to L-870,810, respectively. Phenotypic cross-resistance against the DKA analogue CHI-1043 and MK-0518 was modest but that against GS-9137 was pronounced. Recombination of the mutant integrase genes into the wild-type background reproduced the resistance profile of the resistant IIIB/L-870,810 strains. In addition, resistance against L-870,810 was accompanied by reduced viral replication kinetics and reduced enzymatic activity of integrase. In conclusion, the accumulation of L74M, E92Q, and S230N mutations in the integrase causes resistance to the naphthyridine L-870,810 and cross-resistance to GS-9137. These data may have implications for cross-resistance of different integrase inhibitors in the clinic.
ISSN: 0066-4804
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Molecular Virology and Gene Therapy
Biochemistry, Molecular and Structural Biology Section
× corresponding author
# (joint) last author

Files in This Item:
File Description Status SizeFormat
Mutations in human (2008).pdf Published 331KbAdobe PDFView/Open Request a copy

These files are only available to some KU Leuven Association staff members


All items in Lirias are protected by copyright, with all rights reserved.

© Web of science