Evolution of AZT resistance in HIV-1: the 41-70 intermediate that is not observed in vivo has a replication defect.
The human immunodeficiency virus type 1 (HIV-1) is notorious for its ability to evolve drug-resistance in patients treated with potent antivirals. Resistance to inhibitors of the viral reverse transcriptase (RT) enzyme is frequently mediated by a single amino acid substitution within RT. Resistance against the nucleoside analogue AZT is remarkable in that multiple amino acid changes accumulate over time to yield virus variants with high-level drug resistance. We now report that in addition to drug-resistance properties, the relative replication capacity of the virus variants affects the evolution of AZT resistance. Some of the typical AZT-resistance mutations have a negative impact on virus replication, and the 41-70 double mutant was found to represent a particularly poor virus. Furthermore, introduction of additional AZT-resistance mutations (41-70-215) leads to nearly complete restoration of virus replication. These results may explain the absence of the 41-70 double mutant in clinical samples and indicate that the evolution of AZT resistance is also influenced by virus replication parameters. Prolonged passage of the replication-impaired 41-70 virus in the absence of AZT yielded several fast-replicating variants. These revertants have compensatory changes in the RT polymerase, some of which have been observed previously in AZT-treated patients. Because we could select for these changes without drug pressure, these changes are likely to improve the RT enzyme function and the HIV-1 replication capacity.
Jeeninga
R E
RE
Department of Human Retrovirology, Academic Medical Center, University of Amsterdam, The Netherlands.
Keulen
W
W
Boucher
C
C
Sanders
R W
RW
Berkhout
B
B
D019380:Anti-HIV Agents / Q000494:pharmacology* / Q000627:therapeutic use; D004352:Drug Resistance, Microbial / Q000235:genetics; D019143:Evolution, Molecular; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000737:chemistry / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000502:physiology; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D010641:Phenotype; D011487:Protein Conformation; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D014779:Virus Replication; D015215:Zidovudine / Q000494:pharmacology* / Q000627:therapeutic use
D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine; D054303:HIV Reverse Transcriptase