6mkl | pdb_00006mkl
X-ray crystal structure of darunavir-resistant-P51 HIV-1 protease in complex with GRL-142
Structural highlights
Publication Abstract from PubMedWe attempted to select HIV-1 variants resistant to darunavir (DRV), which potently inhibits the enzymatic activity and dimerization of protease and has a high genetic barrier to HIV-1 development of resistance to DRV. We conducted selection using a mixture of 8 highly multi-protease inhibitor (PI)-resistant, DRV-susceptible clinical HIV-1 variants (HIV-1(MIX)) containing 9 to 14 PI resistance-associated amino acid substitutions in protease. HIV-1(MIX) became highly resistant to DRV, with a 50% effective concentration (EC(50)) approximately 333-fold greater than that against HIV-1(NL4-3). HIV-1(MIX) at passage 51 (HIV-1(MIX(P51))) replicated well in the presence of 5 muM DRV and contained 14 mutations. HIV-1(MIX(P51)) was highly resistant to amprenavir, indinavir, nelfinavir, ritonavir, lopinavir, and atazanavir and moderately resistant to saquinavir and tipranavir. HIV-1(MIX(P51)) had a resemblance with HIV-1(C) of the HIV-1(MIX) population, and selection using HIV-1(C) was also performed; however, its DRV resistance acquisition was substantially delayed. The H219Q and I223V substitutions in Gag, lacking in HIV-1(C(P51)), likely contributed to conferring a replication advantage on HIV-1(MIX(P51)) by reducing intravirion cyclophilin A content. HIV-1(MIX(P51)) apparently acquired the substitutions from another HIV-1 strain(s) of HIV-1(MIX) through possible homologous recombination. The present data suggest that the use of multiple drug-resistant HIV-1 isolates is of utility in selecting drug-resistant variants and that DRV would not easily permit HIV-1 to develop significant resistance; however, HIV-1 can develop high levels of DRV resistance when a variety of PI-resistant HIV-1 strains are generated, as seen in patients experiencing sequential PI failure, and ensuing homologous recombination takes place. HIV-1(MIX(P51)) should be useful in elucidating the mechanisms of HIV-1 resistance to DRV and related agents. In vitro selection of highly darunavir-resistant and replication-competent HIV-1 variants by using a mixture of clinical HIV-1 isolates resistant to multiple conventional protease inhibitors.,Koh Y, Amano M, Towata T, Danish M, Leshchenko-Yashchuk S, Das D, Nakayama M, Tojo Y, Ghosh AK, Mitsuya H J Virol. 2010 Nov;84(22):11961-9. doi: 10.1128/JVI.00967-10. Epub 2010 Sep 1. PMID:20810732[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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