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

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 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 (Delta G(mut) = -30.0 kcal/mol versus Delta G(wt) = -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.