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

Abstract

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.