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Journal of Virology, January 2001, p. 595-602, Vol. 75, No. 2
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.2.595-602.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Establishment of New Transmissible and
Drug-Sensitive Human Immunodeficiency Virus Type 1 Wild Types due
to Transmission of Nucleoside Analogue-Resistant Virus
Anthony
de
Ronde,1,*
Maaike
van
Dooren,1,
Lia
van der
Hoek,1
Denise
Bouwhuis,1
Esther
de
Rooij,1
Bob
van
Gemen,2
Rob
de
Boer,3 and
Jaap
Goudsmit1
Department of Human Retrovirology, Academic
Medical Center, University of Amsterdam, 1105 AZ
Amsterdam,1 Primagen, 1105 BA
Amsterdam,2 and Theoretical Biology,
Utrecht University, 3584 CH Utrecht,3 The
Netherlands
Received 30 May 2000/Accepted 14 October 2000
Sequence analysis of human immunodeficiency virus type 1 (HIV-1)
from 74 persons with acute infections identified eight strains with
mutations in the reverse transcriptase (RT) gene at positions 41, 67, 68, 70, 215, and 219 associated with resistance to the nucleoside
analogue zidovudine (AZT). Follow-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 (Y) to aspartic acid
(D) or serine (S), with asparagine (N) as a transient intermediate,
indicating the establishment of new wild types. When we introduced
these mutations and the original threonine (T)-containing wild type
into infectious molecular clones and assessed their competitive
advantage in vitro, 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 two molecular
beacons, the addition of AZT or stavudine (d4T) to the viral cultures
favored the 215Y mutant in a dose-dependent manner. Our results
illustrate that infection with nucleoside analogue-resistant HIV leads
in newly infected individuals to mutants that are sensitive to
nucleoside analogues, but only a single mutation removed from
drug-resistant HIV. Such mutants were shown to be transmissible,
stable, and prone to rapid selection for resistance to AZT or d4T as
soon as antiretroviral therapy 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 order to estimate the threat to
long-term efficacy of regimens including nucleoside analogues.
*
Corresponding author. Mailing address: Department of
Human Retrovirology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands. Phone:
31.20.566.8571. Fax: 31.20.566.9080. E-mail:
ronde{at}amc.uva.nl.

Present address: Primagen, 1105 BA Amsterdam, The
Netherlands.
Journal of Virology, January 2001, p. 595-602, Vol. 75, No. 2
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.2.595-602.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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