This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Boyer, P. L.
Right arrow Articles by Hughes, S. H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Boyer, P. L.
Right arrow Articles by Hughes, S. H.

 Previous Article  |  Next Article 

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.


This article has been cited by other articles:

  • Gao, L., Hanson, M. N., Balakrishnan, M., Boyer, P. L., Roques, B. P., Hughes, S. H., Kim, B., Bambara, R. A. (2008). Apparent Defects in Processive DNA Synthesis, Strand Transfer, and Primer Elongation of Met-184 Mutants of HIV-1 Reverse Transcriptase Derive Solely from a dNTP Utilization Defect. J. Biol. Chem. 283: 9196-9205 [Abstract] [Full Text]  
  • Boyer, P. L., Stenbak, C. R., Clark, P. K., Linial, M. L., Hughes, S. H. (2004). Characterization of the Polymerase and RNase H Activities of Human Foamy Virus Reverse Transcriptase. J. Virol. 78: 6112-6121 [Abstract] [Full Text]  
  • Diallo, K., Gotte, M., Wainberg, M. A. (2003). Molecular Impact of the M184V Mutation in Human Immunodeficiency Virus Type 1 Reverse Transcriptase. Antimicrob. Agents Chemother. 47: 3377-3383 [Full Text]  
  • Balestrieri, E., Forte, G., Matteucci, C., Mastino, A., Macchi, B. (2002). Effect of Lamivudine on Transmission of Human T-Cell Lymphotropic Virus Type 1 to Adult Peripheral Blood Mononuclear Cells In Vitro. Antimicrob. Agents Chemother. 46: 3080-3083 [Abstract] [Full Text]  
  • Boyer, P. L., Sarafianos, S. G., Arnold, E., Hughes, S. H. (2002). Nucleoside Analog Resistance Caused by Insertions in the Fingers of Human Immunodeficiency Virus Type 1 Reverse Transcriptase Involves ATP-Mediated Excision. J. Virol. 76: 9143-9151 [Abstract] [Full Text]  
  • NIESTERS, H. G. M., DE MAN, R. A., PAS, S. D., FRIES, E., OSTERHAUS, A. D. M. E. (2002). Identification of a new variant in the YMDD motif of the hepatitis B virus polymerase gene selected during lamivudine therapy. J Med Microbiol 51: 695-699 [Abstract] [Full Text]  
  • Rinke, C. S., Boyer, P. L., Sullivan, M. D., Hughes, S. H., Linial, M. L. (2002). Mutation of the Catalytic Domain of the Foamy Virus Reverse Transcriptase Leads to Loss of Processivity and Infectivity. J. Virol. 76: 7560-7570 [Abstract] [Full Text]  
  • Boyer, P. L., Sarafianos, S. G., Arnold, E., Hughes, S. H. (2002). The M184V Mutation Reduces the Selective Excision of Zidovudine 5'-Monophosphate (AZTMP) by the Reverse Transcriptase of Human Immunodeficiency Virus Type 1. J. Virol. 76: 3248-3256 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»