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

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

    Fingerprint

Keywords

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

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this