title: Human immunodeficiency virus type-1 integrase containing a glycine to serine mutation at position 140 is attenuated for catalysis and resistant to integrase inhibitors.
abstract: L-chicoric acid (L-CA) is a potent inhibitor of HIV integrase (IN) in vitro. In this report, the effects of a glycine to serine mutation at position 140 (G140S) on HIV IN and its effects on IN inhibitor resistance are described. HIV containing the G140S mutation showed a delay in replication. Using real-time polymerase chain reaction, the delay was secondary to a failure in integration. The mutant protein (IN(G140S)) was attenuated approximately four-fold for catalysis under equilibrium conditions compared to wild-type IN (IN(WT)) and attenuated five-fold in steady-state kinetic analysis of disintegration. Fifty percent inhibitory concentration assays were performed with IN inhibitors against both IN proteins in disintegration and strand transfer reactions. IN(G140S) was resistant to both L-CA and L-731,988, a diketoacid. HIV containing the mutation was resistant to both inhibitors as well. The G140S mutation attenuates IN activity and confers resistance to IN inhibitors, suggesting that diketoacids and L-CA interact with a similar binding site on HIV IN.
authors.affiliation: Microbiology and Molecular Genetics, University of California, Irvine, CA 92697, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: King
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Lee
authors.forename: Ryan A
authors.initials: RA
authors.lastname: Reinke
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Victoria
authors.forename: Keola
authors.initials: K
authors.lastname: Beale
authors.forename: W Edward
authors.initials: WE
authors.lastname: Robinson
mesh_terms: D000090:Acetoacetates / Q000737:chemistry / Q000494:pharmacology*; D019943:Amino Acid Substitution; D002109:Caffeic Acids / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D024882:Drug Resistance, Viral; D019427:HIV Integrase / Q000737:chemistry / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D019428:HIV Integrase Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology; D006801:Humans; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013386:Succinates / Q000737:chemistry / Q000494:pharmacology*; D016662:Virus Integration; D014779:Virus Replication
chemical_list: D000090:Acetoacetates; D002109:Caffeic Acids; D019428:HIV Integrase Inhibitors; C403886:L 731988; D011758:Pyrroles; D013386:Succinates; D019427:HIV Integrase; C100435:chicoric acid