Relative replication fitness of a high-level 3'-azido-3'-deoxythymidine-resistant variant of human immunodeficiency virus type 1 possessing an amino acid deletion at codon 67 and a novel substitution (Thr-->Gly) at codon 69

J Virol. 2000 Dec;74(23):10958-64. doi: 10.1128/jvi.74.23.10958-10964.2000.

Abstract

The combination of an amino acid deletion at codon 67 (delta 67) and Thr-to-Gly change at codon 69 (T69G) in the reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) is associated with high-level resistance to multiple RT inhibitors. To determine the relative contributions of the delta 67 and T69G mutations on viral fitness, we performed a series of studies of HIV replication using recombinant variants. A high-level 3'-azido-3'-deoxythymidine (AZT)-resistant variant containing delta 67 plus T69G/K70R/L74I/K103N/T215F/K219Q in RT replicated as efficiently as wild-type virus (Wt). In contrast, the construct without delta 67 exhibited impaired replication (23% of growth of Wt). A competitive fitness study failed to reveal any differences in replication rates between the delta 67+T69G/K70R/L74I/K103N/T215F/+ ++K219Q mutant and Wt. Evaluation of proviral DNA sequences over a 3-year period in a patient harboring the multiresistant HIV revealed that the T69G mutation emerged in the context of a D67N/K70R/T215F/K219Q mutant backbone prior to appearance of the delta 67 deletion. To assess the impact of this stepwise accumulation of mutations on viral replication, a series of recombinant variants was constructed and analyzed for replication competence. The T69G mutation was found to confer 2',3'-dideoxyinosine resistance at the expense of fitness. Subsequently, the development of the delta 67 deletion led to a virus with improved replication and high-level AZT resistance.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Anti-HIV Agents / pharmacology*
  • Codon*
  • Gene Deletion
  • HIV Reverse Transcriptase / genetics*
  • HIV-1 / drug effects*
  • HIV-1 / genetics
  • Humans
  • Reverse Transcriptase Inhibitors / pharmacology*
  • Virus Replication
  • Zidovudine / pharmacology*

Substances

  • Anti-HIV Agents
  • Codon
  • Reverse Transcriptase Inhibitors
  • Zidovudine
  • HIV Reverse Transcriptase