Dam E, Rochas S, Faudon JL, Cheret A, Essioux L, Hill A, Clavel F; Conference on Retroviruses and Opportunistic Infections (11th : 2004 : San Francisco, Calif.).
Program Abstr Conf Retrovir Oppor Infect 11th 2004 San Franc Calif. 2004 Feb 8-11; 11: abstract no. 622.
Viralliance, Paris, France
BACKGROUND: Previous studies have reported synergistic interaction between LPV and SQV on wild type HIV-1 but this property has not been tested on resistant viruses, which may be the most interesting targets for PI synergy.METHODS: Synergistic interactions between LPV and SQV were tested on a panel of PI-resistant recombinant viruses, using a modified Phenoscript assay. Five viruses were obtained by site-directed mutagenesis and 9 were reconstructed with Gag-Protease sequences from clinical samples. Inhibition by the combination of SQV and LPV was assessed at four fixed molar LPV:SQV ratios; 1:1, 2:1, 4:1, and 8:1. Interactions were calculated using the multiple drug effect equation of Chou and Talalay based on the median effect principle, with the Calcusyn software (Biosoft, UK). This analysis yielded a combination index (CI), as a function of the inhibition rate. Drugs were considered significantly synergistic at a given inhibition rate when the whole 95% confidence interval of the CI from 3 independent experiments was <1.RESULTS: Among the 9 viruses derived from clinical samples, one was mostly resistant to NFV, 3 were mostly resistant to SQV (57- to 132-fold increase in IC90), 4 were mostly resistant to LPV (37- to 81-fold), and 1 was highly resistant to both LPV (70-fold) and SQV (116-fold). The 5 site-directed mutants carried fewer resistance mutations and exhibited low-level resistance to SQV or LPV. No evidence of synergy between SQV and LPV was observed with wild-type virus, with even a weak antagonistic effect (CI = 1.44 at 50% inhibition and 8:1 LPV/SQV ratio). Significant synergy, however, was repeatedly observed for a subset of the resistant viruses exhibiting high LPV resistance, low SQV resistance, and genotypes including mutations V82A and I54V among others. Synergy was significantly associated with phenotypes yielding SQV/LPV IC90 ratios <0.50 (p = 0.004, Mann-Whitney). In these viruses, highest synergy was found at high LPV/SQV molar ratios (4:1 and 8:1) and at lower inhibition rates. Thus, LPV appears to enhance the antiviral activity of SQV, either at the enzymatic or at the cellular level, but this phenomenon is only measurable when LPV has lost most of its own antiviral activity and when sufficient susceptibility to SQV is retained.CONCLUSIONS: Unlike wild type virus, significant synergistic interaction between LPV and SQV can be observed in viruses with high resistance to LPV and lower resistance to SQV.
Publication Types:
Keywords:
- Acquired Immunodeficiency Syndrome
- Anti-HIV Agents
- Antiviral Agents
- Genes, gag
- Genotype
- HIV
- HIV Antibodies
- HIV Infections
- HIV Protease
- HIV Protease Inhibitors
- HIV-1
- Motor Activity
- Mutation
- Phenotype
- Protease Inhibitors
- Pyrimidinones
- Reverse Transcriptase Inhibitors
- Saquinavir
- genetics
- lopinavir
Other ID:
UI: 102271585
From Meeting Abstracts