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Antimicrobial Agents and Chemotherapy, March 2000, p. 568-573, Vol. 44, No. 3
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
A Novel Human Immunodeficiency Virus Type 1 Reverse Transcriptase
Mutational Pattern Confers Phenotypic Lamivudine Resistance in the
Absence of Mutation 184V
Kurt
Hertogs,1,*
Stuart
Bloor,2
Veronique
De
Vroey,1
Christel
van den
Eynde,1
Pascale
Dehertogh,1
Anja
van
Cauwenberge,1
Martin
Stürmer,3
Timothy
Alcorn,4
Scott
Wegner,5
Margriet
van
Houtte,1
Veronica
Miller,3 and
Brendan
A.
Larder2
Virco NV, Mechelen,
Belgium1; Virco Ltd., Cambridge, United
Kingdom2; Klinikum der J.W.
Goethe-Universität, Zentrum der Inneren Medizin, Frankfurt,
Germany3; LabCorp, Center for Molecular
Biology and Pathology, Research Triangle Park, North
Carolina4; and U.S. Military HIV
Research Program, Rockville, Maryland5
Received 1 July 1999/Returned for modification 22 September
1999/Accepted 9 December 1999
We describe a new human immunodeficiency virus type 1 (HIV-1)
mutational pattern associated with phenotypic resistance
to lamivudine (3TC) in the absence of the characteristic replacement of
methionine by valine at position 184 (M184V) of reverse transcriptase. Combined genotypic and phenotypic analyses of clinical isolates revealed the presence of moderate levels of phenotypic resistance (between 4- and 50-fold) to 3TC in a subset of isolates that did not
harbor the M184V mutation. Mutational cluster analysis and comparison
with the phenotypic data revealed a significant correlation between
moderate phenotypic 3TC resistance and an increased
incidence of replacement of glutamic acid by aspartic acid or alanine
and of valine by isoleucine at residues 44 and 118 of reverse
transcriptase, respectively. This occurred predominantly in those
isolates harboring zidovudine resistance-associated mutations
(41L, 215Y). The requirement of the combination of mutations 41L and
215Y with mutations 44D and 44A and/or 118I for phenotypic 3TC
resistance was confirmed by site-directed mutagenesis experiments.
These data support the assumption that HIV-1 may have access to several
different genetic pathways to escape drug pressure or that the increase
in the frequency of particular mutations may affect susceptibility to
drugs that have never been part of a particular regimen.
*
Corresponding author. Mailing address: Virco NV,
Generaal De Wittelaan 11 B4, B-2800 Mechelen, Belgium. Phone: 32 15 28 63 20. Fax: 32 15 28 63 46. E-mail:
kurt.hertogs{at}virco.be.
Antimicrobial Agents and Chemotherapy, March 2000, p. 568-573, Vol. 44, No. 3
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
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