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Journal of Virology, January 2000, p. 1023-1028, Vol. 74, No. 2
0022-538X/00/$04.00+0

High-Level Resistance to 3'-Azido-3'-Deoxythimidine due to a Deletion in the Reverse Transcriptase Gene of Human Immunodeficiency Virus Type 1

Tomozumi Imamichi,1 Tanima Sinha,1 Hiromi Imamichi,1 Yi-Ming Zhang,1 Julie A. Metcalf,2 Judith Falloon,2 and H. Clifford Lane2,*

SAIC Frederick, Frederick Cancer Research and Development Center, National Cancer Institute, Frederick,1 and Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, Bethesda,2 Maryland

Received 26 April 1999/Accepted 13 October 1999

A variant of human immunodeficiency virus type 1 (HIV-1) possessing a deletion in the reverse transcriptase (RT) gene at codon 67 was identified in a patient who had failed combination antiretroviral therapy. This deletion initially emerged under the selective pressure of combination therapy with 3'-azido-3'-deoxythymidine (AZT) plus 2',3'-dideoxyinosine. It has persisted for more than 3 years in association with the accumulation of a variety of other well-described drug resistance mutations and an uncharacterized mutation at RT codon 69 (T69G). Phenotypic studies demonstrated that the codon 67 deletion by itself had little effect on AZT sensitivity. However, in the context of the T69G mutation and three other mutations known to be associated with AZT resistance (K70R, T215F, and K219Q), this deletion led to a increase in AZT resistance from 8.5-fold to 445-fold. A further increase in resistance (up to 1,813-fold) was observed when two mutations associated with nonnucleoside RT inhibitor resistance (K103N and L74I) were added to the deletion T69G K70R T215F K219Q construct. Hence, these results establish that a deletion at RT codon 67 may be selected for in the presence of antiretroviral therapy and may lead to high-level resistance to AZT.

* Corresponding author. Mailing address: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, 10 Center Dr., Rm. 11S231, Bethesda, MD 20892. Phone: (301) 496-7196. Fax: (301) 480-5560. E-mail: CLANE{at}niaid.nih.gov.

Journal of Virology, January 2000, p. 1023-1028, Vol. 74, No. 2
0022-538X/00/$04.00+0


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