Exploitation of the low fidelity of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase and the nucleotide composition bias in the HIV-1 genome to alter the drug resistance development of HIV

The RNA genome of the lentivirus human immunodeficiency virus type 1 (HIV-1 ) is significantly richer in adenine nucleotides than the statistically equ al distribution of the four different nucleotides that is expected. This co mpositional bias may be due to the guanine-to-adenine (G -->A) nucleotide h ypermutation of the HIV genome, which has been explained by dCTP pool imbal ances during reverse transcription. The adenine nucleotide bias together wi th the poor fidelity of HIV-1 reverse transcriptase markedly enhances the g enetic variation of HIV and may be responsible for the rapid emergence of d rug-resistant HIV-1 strains. We have now attempted to counteract the normal mutational pattern of HIV-1 in response to anti-HIV-1 drugs by altering th e endogenous deoxynucleoside triphosphate pool ratios with antimetabolites in virus-infected cell cultures. We showed that administration of these ant imetabolic compounds resulted in an altered drug resistance pattern due to the reversal of the predominant mutational flow of HIV (G -->A) to an adeni ne-to-guanine (A -->G) nucleotide pattern in the intact HIV-1-infected lymp hocyte cultures. Forcing the virus to change its inherent nucleotide bias m ay lead to better control of viral drug resistance development.