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Journal of Virology, July 2001, p. 6321-6328, Vol. 75, No. 14
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.14.6321-6328.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

YADD Mutants of Human Immunodeficiency Virus Type 1 and Moloney Murine Leukemia Virus Reverse Transcriptase Are Resistant to Lamivudine Triphosphate (3TCTP) In Vitro

Paul L. Boyer,1 Hong-Qiang Gao,1,dagger Patrick K. Clark,2 Stefan G. Sarafianos,3 Edward Arnold,3 and Stephen H. Hughes1,*

HIV Drug Resistance Program1 and SAIC Frederick,2 National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Maryland 21702-1201, and Center for Advanced Biotechnology and Medicine and Rutgers University Chemistry Department, Piscataway, New Jersey 08854-56383

Received 5 January 2001/Accepted 12 April 2001

When human immunodeficiency virus type 1 (HIV-1) is selected for resistance to 3TC, the methionine normally present at position 184 is replaced by valine or isoleucine. Position 184 is the X of the conserved YXDD motif; positions 185 and 186 form part of the triad of aspartic acids at the polymerase active site. Structural and biochemical analysis of 3TC-resistant HIV-1 reverse transcriptase (RT) led to a model in which a beta -branched amino acid at position 184 would act as a steric gate. Normal deoxynucleoside triphosphates (dNTPs) could still be incorporated; the oxathiolane ring of 3TCTP would clash with the beta  branch of the amino acid at position 184. This model can also explain 3TC resistance in feline immunodeficiency virus and human hepatitis B virus. However, it has been reported (14) that murine leukemia viruses (MLVs) with valine (the amino acid present in the wild type), isoleucine, alanine, serine, or methionine at the X position of the YXDD motif are all resistant to 3TC. We prepared purified wild-type MLV RT and mutant MLV RTs with methionine, isoleucine, and alanine at the X position. The behavior of these RTs was compared to those of wild-type HIV-1 RT and of HIV-1 RT with alanine at the X position. If alanine is present at the X position, both MLV RT and HIV-1 RT are relatively resistant to 3TCTP in vitro. However, the mutant enzymes were impaired relative to their wild-type counterparts; there appears to be steric hindrance for both 3TCTP and normal dNTPs.

* Corresponding author. Mailing address: HIV Drug Resistance Program, National Cancer Institute-FCRDC, P.O. Box B, Building 539, Room 130A, Frederick, MD 21702-1201. Phone: (301) 846-1619. Fax: (301) 846-6966. E-mail: hughes{at}ncifcrf.gov.

dagger Present address: E-Centive, Bethesda, MD 20817.

Journal of Virology, July 2001, p. 6321-6328, Vol. 75, No. 14
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.14.6321-6328.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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