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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 susceptibilities and genotypes of nearly 900 human immunodeficiency virus type 1 (HIV-1) samples. For 302 of these, the 50% inhibitory concentrations of at least four of the approved nucleoside analogs had fourfold-or-greater increases. Genotypic analysis of the reverse transcriptase (RT)-coding regions from these samples revealed complex mutational patterns, including the previously recognized codon 151 multidrug resistance cluster. Surprisingly, high-level multinucleoside resistance was associated with a diverse family of amino acid insertions in addition to "conventional" point mutations. These insertions were found between RT codons 67 and 70 and were commonly 69Ser-(Ser-Ser) or 69Ser-(Ser-Gly). Treatment history information showed that a common factor for the development of these variants was AZT (3'-azido-3'-deoxythymidine, zidovudine) therapy in combination with 2',3'-dideoxyinosine or 2',3'-dideoxycytidine, although treatment patterns varied considerably. Site-directed mutagenesis studies confirmed that 69Ser-(Ser-Ser) in an AZT resistance mutational background conferred simultaneous resistance to multiple nucleoside analogs. The insertions are located in the "fingers" domain of RT. Modelling the 69Ser-(Ser-Ser) insertion into the RT structure demonstrated the profound direct effect that this change is likely to have in the nucleoside triphosphate binding site of the enzyme. Our data highlight the increasing problem of HIV-1 multidrug resistance and underline the importance of continued resistance surveillance with appropriate, sufficiently versatile genotyping technology and phenotypic drug susceptibility analysis.

* 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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