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Journal of Virology, December 2000, p. 10958-10964, Vol. 74, No. 23
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Relative Replication Fitness of a High-Level 3'-Azido-3'-Deoxythymidine-Resistant Variant of Human Immunodeficiency Virus Type 1 Possessing an Amino Acid Deletion at Codon 67 and a Novel Substitution (Thrright-arrow Gly) at Codon 69

Tomozumi Imamichi,1,* Steve C. Berg,1 Hiromi Imamichi,1 Juan C. Lopez,1,2 Julia A. Metcalf,3 Judith Falloon,3 and H. Clifford Lane3

Laboratory of Molecular Retrovirology, Clinical Services Program, SAIC-Frederick, Frederick Cancer Research and Development Center, Frederick,1 and Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, Bethesda,3 Maryland, and Hospital General Gregorio Maranon, Madrid, Spain2

Received 13 June 2000/Accepted 28 August 2000

The combination of an amino acid deletion at codon 67 (Delta 67) and Thr-to-Gly change at codon 69 (T69G) in the reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) is associated with high-level resistance to multiple RT inhibitors. To determine the relative contributions of the Delta 67 and T69G mutations on viral fitness, we performed a series of studies of HIV replication using recombinant variants. A high-level 3'-azido-3'-deoxythymidine (AZT)-resistant variant containing Delta 67 plus T69G/K70R/L74I/K103N/T215F/K219Q in RT replicated as efficiently as wild-type virus (Wt). In contrast, the construct without Delta 67 exhibited impaired replication (23% of growth of Wt). A competitive fitness study failed to reveal any differences in replication rates between the Delta 67+T69G/K70R/L74I/K103N/T215F/K219Q mutant and Wt. Evaluation of proviral DNA sequences over a 3-year period in a patient harboring the multiresistant HIV revealed that the T69G mutation emerged in the context of a D67N/K70R/T215F/K219Q mutant backbone prior to appearance of the Delta 67 deletion. To assess the impact of this stepwise accumulation of mutations on viral replication, a series of recombinant variants was constructed and analyzed for replication competence. The T69G mutation was found to confer 2',3'-dideoxyinosine resistance at the expense of fitness. Subsequently, the development of the Delta 67 deletion led to a virus with improved replication and high-level AZT resistance.

* Corresponding author. Mailing address: Building 550, Room 126, SAIC-Frederick, NCI-FCRDC, P.O. Box B, Frederick, MD 21702. Phone: (301) 846-5450. Fax: (301) 846-6762. E-mail: timamichi{at}nih.gov.

Journal of Virology, December 2000, p. 10958-10964, Vol. 74, No. 23
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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