TY - JOUR
T1 - Processivity and drug-dependence of HIV-1 protease
T2 - Determinants of viral fitness in variants resistant to protease inhibitors
AU - Menzo, Stefano
AU - Monachetti, Alessia
AU - Balotta, Claudia
AU - Corvasce, Stefano
AU - Rusconi, Stefano
AU - Paolucci, Stefania
AU - Baldanti, Fausto
AU - Bagnarelli, Patrizia
AU - Clementi, Massimo
PY - 2003/3/28
Y1 - 2003/3/28
N2 - Objective: To investigate the role of processivity and drug-dependence of HIV-1 protease as fitness determinants in variants resistant to protease inhibitors (PI). Design and methods: HIV-1 protease sequences from 32 infected subjects (27 patients who failed PI-treatments and five PI-naive controls) were evaluated using a recombinant method. The HIV-1 phenotype to seven PI was analysed together with the replication capacity of recombinants and the processivity and drug-dependence of the HIV-1 proteases. Protease mutants (positions 10, 46, 54, 82, 84, 90, and combinations thereof) were generated in vitro and studied under identical experimental conditions. Results: In the absence of PI, 24 of 27 (89%) resistant proteases from treated subjects showed decreased processivity compared with the wild type. Processivity was lower in sequences bearing fewer mutations, than in more mutated ones. Twelve sequences (44%) conferred slower replication kinetics to the recombinant viruses. Seven sequences (26%) showed higher processivity levels in the presence of PI than in their absence, suggesting that drug-dependence influences PI-resistant variants. Among the mutants generated in vitro, mutations 82A and 90M determined broad cross-resistance to PI in association with 101. A drop of processivity was observed for the 82A+90M variants; 101 allowed partial recovery for 82A and 84V, and marked recovery for 90M mutants. Conclusions: A decrease in HIV-1 protease processivity parallels early selection of primary mutations, whereas its recovery is driven by compensatory mutations. Furthermore, a PI may select drug-dependent, besides resistant, HIV-1 protease variants. Changes in processivity and drug-dependence of HIV-1 proteases have implications in the replication capacity of PI-resistant viruses.
AB - Objective: To investigate the role of processivity and drug-dependence of HIV-1 protease as fitness determinants in variants resistant to protease inhibitors (PI). Design and methods: HIV-1 protease sequences from 32 infected subjects (27 patients who failed PI-treatments and five PI-naive controls) were evaluated using a recombinant method. The HIV-1 phenotype to seven PI was analysed together with the replication capacity of recombinants and the processivity and drug-dependence of the HIV-1 proteases. Protease mutants (positions 10, 46, 54, 82, 84, 90, and combinations thereof) were generated in vitro and studied under identical experimental conditions. Results: In the absence of PI, 24 of 27 (89%) resistant proteases from treated subjects showed decreased processivity compared with the wild type. Processivity was lower in sequences bearing fewer mutations, than in more mutated ones. Twelve sequences (44%) conferred slower replication kinetics to the recombinant viruses. Seven sequences (26%) showed higher processivity levels in the presence of PI than in their absence, suggesting that drug-dependence influences PI-resistant variants. Among the mutants generated in vitro, mutations 82A and 90M determined broad cross-resistance to PI in association with 101. A drop of processivity was observed for the 82A+90M variants; 101 allowed partial recovery for 82A and 84V, and marked recovery for 90M mutants. Conclusions: A decrease in HIV-1 protease processivity parallels early selection of primary mutations, whereas its recovery is driven by compensatory mutations. Furthermore, a PI may select drug-dependent, besides resistant, HIV-1 protease variants. Changes in processivity and drug-dependence of HIV-1 proteases have implications in the replication capacity of PI-resistant viruses.
KW - Drug-dependence
KW - Enzyme processivity
KW - HIV-1 fitness
KW - Protease inhibitors
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U2 - 10.1097/00002030-200303280-00003
DO - 10.1097/00002030-200303280-00003
M3 - Article
C2 - 12646788
AN - SCOPUS:0037471312
VL - 17
SP - 663
EP - 671
JO - AIDS
JF - AIDS
SN - 0269-9370
IS - 5
ER -