Variations in HIV-1 pol gene associated with reduced sensitivity to antiretroviral drugs in treatment-naive patients

Abstract

Objective: Various drugs against the HIV-1 enzymes reverse transcriptase (RT) and protease have been introduced in the last few years: protease inhibitors, nucleoside RT inhibitors (NRTI) and non-NRTI (NNRTI). Several sequence variations associated with reduced drug sensitivity have been described in the HIV-1 pol gene.

Design: To analyse the occurrence of mutations associated with drug resistance in treatment-naive individuals.

Methods: RNA was extracted from sera of treatment-naive individuals, who were first diagnosed to be HIV-1 infected between August 1996 and February 1998. The pol region was amplified by RT-PCR and directly sequenced. Data on mutations associated with resistance to antiretroviral drugs were obtained from literature.

Results: Fifty protease genes and 53 RT genes from 57 individuals were sequenced. In the RT we analysed 20 amino-acid positions associated with resistance to NRTI and NNRTI. In total, 1054 amino acids at critical positions were analysed and three (0.3%) mutations known to contribute to RTI resistance were detected. In the protease, 16 amino-acid positions associated with resistance to protease inhibitors were analysed. By analysing a total of 768 amino acids at key positions in the protease, 50 (7%) mutations were detected that were associated with reduced drug sensitivity. Thirty-one (61%) patients showed between one and six mutations at the analysed protease amino-acid positions. In eight out of 16 analysed amino-acid positions, up to 44% of all patients carried mutations associated with resistance to protease inhibitors.

Conclusions: Very few pre-existing mutations to RTI were found, suggesting that the transmission of RT-resistant strains is still uncommon. However, about two-thirds of the patients had one or more mutations associated with resistance to protease inhibitors. In addition, at some amino-acid positions up to almost half of the patients carried variations claimed to contribute to protease inhibitor resistance. Most of these mutations are likely to reflect the natural polymorphism of the protease. Their impact on the long-term effect of antiretroviral treatment should be evaluated in future studies.