TY - JOUR

T1 - Immunological responses during a virologically failing antiretroviral regimen are associated with in vivo synonymous mutation rates of HIV type-1 env

AU - Mens, Helene

AU - Jørgensen, Louise Bruun

AU - Kronborg, Gitte

AU - Schønning, Kristian

AU - Benfield, Thomas

PY - 2009

Y1 - 2009

N2 - 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 > or =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.

AB - 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 > or =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.

M3 - Journal article

VL - 14

SP - 413

EP - 422

JO - Antiviral Therapy

JF - Antiviral Therapy

SN - 1359-6535

IS - 3

ER -