Immunological responses during a virologically failing antiretroviral regimen are associated with in vivo synonymous mutation rates of HIV type-1 env.

Background: Little is known about the underlying causes of differences in immunological response to antiretroviral therapy during multidrug-resistant (MDR) HIV type-1 (HIV-1) infection. This study aimed to identify virological factors associated with immunological response during therapy failure. Methods: Individuals with MDR HIV-1 receiving therapy for >= 3 months were included. CD4(+) T-cell count slopes and pol and clonal env sequences were determined. Genetic analyses were performed using distance-based and maximum likelihood methods. Synonymous mutations rates of env were used to estimate viral replication. Results: Of 1,000 patients treated between 1995 and 2003, 72 individuals fulfilled the definition for triple-class failure, but 25 were non-compliant, 21 were successfully resuppressed and 3 had died or quit therapy. Of the 23 that fulfilled study criteria, 16 had samples available for analysis. In a longitudinal mixed-effects model, plasma HIV-1 RNA only tended to predict immunological response (P=0.06), whereas minor protease inhibitor (PI) and nucleoside reverse transcriptase (NRTI) mutations at baseline correlated significantly with CD4(+) T-cell count slopes (r=-0.56, P=0.04 and r=-0.64, P=0.008, respectively). Interestingly, synonymous mutations of env correlated inversely with CD4(+) T-cell count slopes (r=-0.60; P=0.01) and individuals with codons under positive selection had significantly better CD4(+) T-cell responses than individuals without (0.42 versus -5.34; P=0.02). Conclusions: Our results suggest that minor PI mutations and NRTI mutations present early during therapy failure are predictive of the CD4(+) T-cell count slopes. Synonymous mutation rates of the env gene suggested that underlying differences in fitness could cause this association.