Mutations in the non-nucleoside binding-pocket interfere with the multi-nucleoside resistance phenotype

Area of Science:

• Virology
• Molecular Biology
• Drug Resistance

Background:

• HIV-1 drug resistance is a major challenge in antiretroviral therapy.
• The Q151M mutation confers multi-nucleoside resistance.
• Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are a key component of HIV-1 treatment regimens.

Purpose of the Study:

• To investigate the genotypic and phenotypic effects of in vitro resistance selection with lamivudine and the NNRTI quinoxaline HBY097.
• To analyze resistance patterns in HIV-1 isolates with the Q151M multi-nucleoside resistance mutation.

Main Methods:

• HIV-1 strains were selected in cell culture with increasing concentrations of lamivudine or HBY097.
• The reverse transcriptase gene was sequenced to identify resistance mutations.
• Antiviral activities of drugs were evaluated phenotypically.

Main Results:

• High-level resistance to lamivudine and HBY097 developed rapidly (less than 10 passages).
• Lamivudine selected for the M184I mutation, increasing resistance to nucleoside analog reverse transcriptase inhibitors (NRTIs).
• NNRTI resistance mutations partially reversed NRTI resistance, with complex effects depending on the specific mutations present.

Conclusions:

• Changes in the non-nucleoside binding pocket influence the dNTP binding site conformation.
• This conformational change can lead to a partial reversal of the multi-nucleoside resistance phenotype.