Biological testing versus sequence analysis for determination of drug resistance of human immunodeficiency virus

Resistance of HIV-1 to 3'-azido-3'-deoxythymidine (AZT) is associated with one or more of five mutations in the reverse transcriptase (RT) segment of the polymerase gene ("AZT-specific mutations"). Therefore, sequence analysis of the proviral DNA, derived directly from the blood, is considered to replace the biological test. Additional arguments are non-cultivatable viral strains, the universality of the sequence analysis in combination therapy, and the suspicion that the cultivated virus does not represent the predominant viral variant in the blood. In this investigation, 21 strains of human immunodeficiency virus type 1 (HIV-1) were comparatively analysed by molecular and biological testing. For 12 strains, the homology of the RT gene segment between the predominant provirus in the blood and the cultivated virus was ascertained (99.72% homology). 11 strains from untreated patients or patients treated no longer than 5 months were free from AZT-specific mutations and proved to be sensitive. 10 strains from patients treated for 17 to 57 months displayed 2-4 AZT-specific mutations. However, it was not possible to correlate the degree of sensitivity to the number or the pattern of the mutations. Suppression of AZT resistance by strain-specific sequences in other parts of the gene are discussed as the reason for that discrepancy. Remarkably, the productivity of resistant virus strains could be drastically enhanced by non-inhibiting concentrations of the drug.