title: 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.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  The prevalence of protease-compensatory mutations from 1997 to 2011 was 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.
  
  
  RESULTS
  The number of HIV-1 B-infected patients with at least one protease-compensatory mutation increased over time (from 86.4% prior to 2001 to 92.6% after 2009, P = 0.02). 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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Experimental Medicine and Surgery, University of Rome 'Tor Vergata', Rome, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Alteri
authors.forename: Anna
authors.initials: A
authors.lastname: Artese
authors.forename: Gertjan
authors.initials: G
authors.lastname: Beheydt
authors.forename: Maria Mercedes
authors.initials: MM
authors.lastname: Santoro
authors.forename: Giosuè
authors.initials: G
authors.lastname: Costa
authors.forename: Lucia
authors.initials: L
authors.lastname: Parrotta
authors.forename: Ada
authors.initials: A
authors.lastname: Bertoli
authors.forename: Caterina
authors.initials: C
authors.lastname: Gori
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Orchi
authors.forename: Enrico
authors.initials: E
authors.lastname: Girardi
authors.forename: Andrea
authors.initials: A
authors.lastname: Antinori
authors.forename: Stefano
authors.initials: S
authors.lastname: Alcaro
authors.forename: Antonella
authors.initials: A
authors.lastname: d'Arminio Monforte
authors.forename: Kristof
authors.initials: K
authors.lastname: Theys
authors.forename: Anne-Mieke
authors.initials: AM
authors.lastname: Vandamme
authors.forename: Francesca
authors.initials: F
authors.lastname: Ceccherini-Silberstein
authors.forename: Valentina
authors.initials: V
authors.lastname: Svicher
authors.forename: Carlo Federico
authors.initials: CF
authors.lastname: Perno
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D016333:HIV Protease / Q000235:genetics*; D015497:HIV-1 / Q000235:genetics* / Q000302:isolation & purification; D006801:Humans; D061466:Lopinavir / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D019438:Ritonavir / Q000627:therapeutic use*; D013489:Suppression, Genetic; D016896:Treatment Outcome; D019562:Viral Load
chemical_list: D019380:Anti-HIV Agents; D061466:Lopinavir; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1; D019438:Ritonavir
keywords: antiviral; drug resistance; molecular modelling