Establishment of new transmissible and drug-sensitive human immunodeficiency virus type 1 wild types due to transmission of nucleoside analogue-resistant virus

Sequence analysis of human immunodeficiency virus type 1 (HIV-1) from 74 pe rsons with acute infections identified eight strains with mutations in the reverse transcriptase (RT) gene at positions ill, 67, 68, 70, 215, and 219 associated with resistance to the nucleoside analogue zidovudine (AZT), Fol low-up of the fate of these resistant HIV-1 strains in four newly infected individuals revealed that they were readily replaced by sensitive strains, The RT of the resistant viruses changed at amino acid 215 from tyrosine Oil to aspartic acid (D) or serine (S), with asparagine (N) as a transient int ermediate, indicating the establishment of new wild types, When we introduc ed these mutations and the original threonine (T)-containing wild type into infectious molecular clones and assessed their competitive advantage in vi tro, the order of fitness was in accord with the in vivo observations: 215Y < 215D = 215S = 215T. As detected by real-time nucleic acid sequence-based amplification with typo molecular beacons, the addition of AZT or stavudin e (d4T) to the viral cultures favored the 215Y mutant in a dose-dependent m anner. Our results illustrate that infection with nucleoside analogue-resis tant HIV leads in newly infected individuals to mutants that are sensitive to nucleoside analogues, but only a single mutation removed from drug-resis tant HIV, Such mutants were shown to be transmissible, stable, and prone to rapid selection for resistance to AZT or d4T as soon as antiretroviral the rapy was administered, Monitoring of patients for the presence of new HIV-1 wild types with D, S, or N residues at position 215 may be warranted in or der to estimate the threat to long-term efficacy of regimens including nucl eoside analogues.