Structural modifications induced by specific HIV-1 protease-compensatory mutations have an impact on the virological response to a first-line lopinavir/ritonavir-containing regimen

Claudia Alteri, Anna Artese, Gertjan Beheydt, Maria Mercedes Santoro, Giosué Costa, Lucia Parrotta, Ada Bertoli, Caterina Gori, Nicoletta Orchi, Enrico Girardi, Andrea Antinori, Stefano Alcaro, Antonella D.Arminio Monforte, Kristof Theys, Anne Mieke Vandamme, Francesca Ceccherini-Silberstein, Valentina Svicher, Carlo Federico Perno

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9 Citations (Scopus)

Abstract

Objectives: This study evaluates the impact of specific HIV-1 protease-compensatory mutations (wild-type amino acids in non-B subtypes) on virological response to a first-line lopinavir/ritonavir-containing regimen in an HIV-1 subtype B-infected population. Patients and methods: The prevalence of protease-compensatory mutations from1997 to 2011was calculated in 3063 drug-naive HIV-1 B-infected patients. The role of these mutations on virological outcome is estimated in a subgroup of 201 patients starting their first lopinavir/ritonavir-containing regimen by covariation and docking analyses. The number of HIV-1 B-infected patients with at least one protease-compensatory mutation increased over time (from86.4% prior to 2001 to 92.6% after 2009, P1/40.02). Analysing 201 patients starting first-line lopinavir/ritonavir, the median time to virological failure was shorter in patients with at least one protease-compensatory mutation than in patients with no protease-compensatory mutations. By covariation and docking analyses, specific mutations were found to affect lopinavir affinity for HIV-1 protease and to impact virological failure. Specifically, the L10V+I13V+L63P+I93L cluster, related to fast virological failure, correlated with a decreased drug affinity for the enzyme in comparison with wild-type (ΔGmut=-30.0 kcal/mol versus ΔGwt=-42.3 kcal/mol). Our study shows an increased prevalence of specific protease-compensatory mutations in an HIV-1 B-infected population and confirms that their copresence can affect the virological outcome in patients starting a lopinavir/ritonavir-containing regimen.

Original languageEnglish
Article numberdkt173
Pages (from-to)2203-2209
Number of pages7
JournalJournal of Antimicrobial Chemotherapy
Volume68
Issue number10
DOIs
Publication statusPublished - 1 Oct 2013

Keywords

  • Antiviral
  • Drug resistance
  • Molecular modelling

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