Resistance to ddI and Sensitivity to AZT Induced by a Mutation in HIV-1 Reverse Transcriptase

TLDR

Combination therapy for HIV‑1 may prevent the emergence of drug‑resistant isolates. The study followed serial HIV‑1 isolates from five AIDS patients who switched from AZT to ddI after ≥12 months of AZT therapy. A reverse‑transcriptase mutation reduced ddI sensitivity, and when co‑occurring with an AZT‑resistance mutation it increased AZT sensitivity; the ddI‑resistance mutation alone conferred resistance to ddI and dCyd and suppressed the AZT‑resistance effect.

Abstract

Serial human immunodeficiency virus type-1 (HIV-1) isolates were obtained from five individuals with acquired immunodeficiency syndrome (AIDS) who changed therapy to 2',3'-dideoxyinosine (ddI) after at least 12 months of treatment with 3'-azido-3'-deoxythymidine (zidovudine, AZT). The in vitro sensitivity to ddI decreased during the 12 months following ddI initiation, whereas AZT sensitivity increased. Analysis of the reverse transcriptase coding region revealed a mutation associated with reduced sensitivity to ddI. When this mutation was present in the same genome as a mutation known to confer AZT resistance, the isolates showed increased sensitivity to AZT. Analysis of HIV-1 variants confirmed that the ddI resistance mutation alone conferred ddI and 2',3'-dideoxycytidine resistance, and suppressed the effect of the AZT resistance mutation. The use of combination therapy for HIV-1 disease may prevent drug-resistant isolates from emerging.