A Family of Insertion Mutations between Codons 67 and 70 of Human Immunodeficiency Virus Type 1 Reverse Transcriptase Confer Multinucleoside Analog Resistance

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Antimicrobial Agents and Chemotherapy, August 1999, p. 1961-1967, Vol. 43, No. 8
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

A Family of Insertion Mutations between Codons 67 and 70 of Human Immunodeficiency Virus Type 1 Reverse Transcriptase Confer Multinucleoside Analog Resistance

B. A. Larder,¹^,^* S. Bloor,¹ S. D. Kemp,¹ Kurt Hertogs,² R. L. Desmet,² V. Miller,³ M. Sturmer,³ S. Staszewski,³ J. Ren,⁴ D. K. Stammers,⁴ D. I. Stuart,⁴ and R. Pauwels²

Virco UK, Ltd., Cambridge, CB4 4GH,¹ and Laboratory of Molecular Biophysics, University of Oxford, Oxford, OX1 3QU,⁴ United Kingdom; Virco N.V., B-2800, Mechelen, Belgium²; and Goethe Universität, Frankfurt, Germany³

Received 1 February 1999/Returned for modification 26 April 1999/Accepted 27 May 1999

To investigate the occurrence of multinucleoside analog resistance during therapy failure, we surveyed the drug susceptibilitiesand genotypes of nearly 900 human immunodeficiency virus type1 (HIV-1) samples. For 302 of these, the 50% inhibitory concentrationsof at least four of the approved nucleoside analogs had fourfold-or-greaterincreases. Genotypic analysis of the reverse transcriptase (RT)-codingregions from these samples revealed complex mutational patterns,including the previously recognized codon 151 multidrug resistancecluster. Surprisingly, high-level multinucleoside resistance wasassociated with a diverse family of amino acid insertions in additionto "conventional" point mutations. These insertions were foundbetween RT codons 67 and 70 and were commonly 69Ser-(Ser-Ser)or 69Ser-(Ser-Gly). Treatment history information showed thata common factor for the development of these variants was AZT(3'-azido-3'-deoxythymidine, zidovudine) therapy in combinationwith 2',3'-dideoxyinosine or 2',3'-dideoxycytidine, although treatmentpatterns varied considerably. Site-directed mutagenesis studiesconfirmed that 69Ser-(Ser-Ser) in an AZT resistance mutationalbackground conferred simultaneous resistance to multiple nucleosideanalogs. The insertions are located in the "fingers" domain ofRT. Modelling the 69Ser-(Ser-Ser) insertion into the RT structuredemonstrated the profound direct effect that this change is likelyto have in the nucleoside triphosphate binding site of the enzyme.Our data highlight the increasing problem of HIV-1 multidrug resistanceand underline the importance of continued resistance surveillancewith appropriate, sufficiently versatile genotyping technologyand phenotypic drug susceptibilityanalysis.

^* Corresponding author. Mailing address: Virco UK, 184 Cambridge Science Park, Milton Rd., Cambridge, CB4 4GH, United Kingdom.Phone: 44 1 223 728 828. Fax: 44 1 223 728 801. E-mail: brendan.larder{at}virco.co.uk.

Antimicrobial Agents and Chemotherapy, August 1999, p. 1961-1967, Vol. 43, No. 8
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

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