Due to the high genetic variability of human immunodeficiency virus (HIV), treatment of
AIDS (
acquired immunodeficiency syndrome) patients with inhibitors of reverse trancriptase (RT) and drugs blocking the viral
protease regularly results in the accumulation of
drug resistant HIV variants and treatment failure. The sensitivity of clinically derived resistant HIV-1 strains to
nucleotide RT inhibitors could be restored, however, in several laboratories by pharmacological depletion of the appropriate endogenous deoxynucleotide
triphosphate (dNTP), and such a manipulation (induction of
dCTP pool imbalance during reverse transcription in the presence of a non-
nucleoside RT inhibitor) altered the mutation spectrum of the HIV-1 genome, resulting in a lower level of HIV resistance to certain drugs. The cytoplasmic
single-stranded DNA cytidine deaminases APOBEC3G and APOBEC3F block HIV replication by introducing
premature stop codons into the viral genome. We suggest that the resulting crippled, defective HIV (dHIV) variants could interfere with replication of "wild type" viruses and curbe disese progression in long term non-progressor individuals. Vif, an accessory
protein encoded by HIV, counteracts APOBEC3G/F action. We speculate that small molecule inhibitors of Vif could permit lethal or sublethal mutagenesis of HIV genomes. We suggest that an artificial dHIV construct carrying a mutated vif gene (coding for a
Vif protein unable to block APOBEC3G/F) could have a
therapeutic effect as well in HIV infected individuals and
AIDS patients.