Processivity and drug-dependence of HIV-1 protease

Determinants of viral fitness in variants resistant to protease inhibitors

Stefano Menzo, Alessia Monachetti, Claudia Balotta, Stefano Corvasce, Stefano Rusconi, Stefania Paolucci, Fausto Baldanti, Patrizia Bagnarelli, Massimo Clementi

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)663-671
Number of pages9
JournalAIDS (London, England)
Volume17
Issue number5
DOIs
Publication statusPublished - Mar 28 2003

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Protease Inhibitors
Substance-Related Disorders
Mutation
Peptide Hydrolases
Human immunodeficiency virus 1 p16 protease
Viruses
HIV-1
Phenotype

Keywords

  • Drug-dependence
  • Enzyme processivity
  • HIV-1 fitness
  • Protease inhibitors

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Processivity and drug-dependence of HIV-1 protease : Determinants of viral fitness in variants resistant to protease inhibitors. / Menzo, Stefano; Monachetti, Alessia; Balotta, Claudia; Corvasce, Stefano; Rusconi, Stefano; Paolucci, Stefania; Baldanti, Fausto; Bagnarelli, Patrizia; Clementi, Massimo.

In: AIDS (London, England), Vol. 17, No. 5, 28.03.2003, p. 663-671.

Research output: Contribution to journalArticle

Menzo, Stefano ; Monachetti, Alessia ; Balotta, Claudia ; Corvasce, Stefano ; Rusconi, Stefano ; Paolucci, Stefania ; Baldanti, Fausto ; Bagnarelli, Patrizia ; Clementi, Massimo. / Processivity and drug-dependence of HIV-1 protease : Determinants of viral fitness in variants resistant to protease inhibitors. In: AIDS (London, England). 2003 ; Vol. 17, No. 5. pp. 663-671.
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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

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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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