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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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