Mutagenic outcome of combined antiviral drug treatment during human immunodeficiency virus type 1 replication.

The development of antiviral drug resistance is an important problem in the treatment of human immunodeficiency virus type 1 (HIV-1) infection. Potent antiretroviral therapy (ART) is currently used for treatment, and typically consists of at least two reverse transcriptase (RT) inhibitors. To assess the impact of combination therapy on HIV-1 mutagenesis, the mutagenic outcome of combined drug treatment was determined with several different RT drug combinations. Significant increases in HIV-1 mutant frequencies were observed with combinations of nucleoside RT inhibitors as well as in combinations where nucleoside inhibitors were used along with hydroxyurea, a drug known to deplete nucleotide pools in cells. This indicates that combinations of RT drugs can act together to further increase HIV-1 mutant frequencies, which could have important implications for virus population dynamics and could compromise drug therapy regimens.