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Journal of Virology, July 2001, p. 5772-5777, Vol. 75, No. 13
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.13.5772-5777.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Exploitation of the Low Fidelity of Human Immunodeficiency Virus Type 1 (HIV-1) Reverse Transcriptase and the Nucleotide Composition Bias in the HIV-1 Genome To Alter the Drug Resistance Development of HIV

Jan Balzarini,1,* Maria-José Camarasa,2 Maria-Jesus Pérez-Pérez,2 Ana San-Félix,2 Sonsoles Velázquez,2 Carlo-Federico Perno,3 Erik De Clercq,1 John N. Anderson,4 and Anna Karlsson5

Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium1; Instituto de Química Médica, Consejo Superior Investigaciones Cientificas (CSIC), 28006 Madrid, Spain2; Department of Experimental Medicine, University of Rome "Tor Vergata," I-00135 Rome, Italy3; Department of Biological Sciences, Purdue University, West Lafayette, Indiana 479074; and Karolinska Institute, Division of Clinical Virology F68, Huddinge University Hospital, S-141 86 Huddinge/Stockholm, Sweden5

Received 27 December 2000/Accepted 30 March 2001

The RNA genome of the lentivirus human immunodeficiency virus type 1 (HIV-1) is significantly richer in adenine nucleotides than the statistically equal distribution of the four different nucleotides that is expected. This compositional bias may be due to the guanine-to-adenine (Gright-arrowA) nucleotide hypermutation of the HIV genome, which has been explained by dCTP pool imbalances during reverse transcription. The adenine nucleotide bias together with the poor fidelity of HIV-1 reverse transcriptase markedly enhances the genetic variation of HIV and may be responsible for the rapid emergence of drug-resistant HIV-1 strains. We have now attempted to counteract the normal mutational pattern of HIV-1 in response to anti-HIV-1 drugs by altering the endogenous deoxynucleoside triphosphate pool ratios with antimetabolites in virus-infected cell cultures. We showed that administration of these antimetabolic compounds resulted in an altered drug resistance pattern due to the reversal of the predominant mutational flow of HIV (Gright-arrowA) to an adenine-to-guanine (Aright-arrowG) nucleotide pattern in the intact HIV-1-infected lymphocyte cultures. Forcing the virus to change its inherent nucleotide bias may lead to better control of viral drug resistance development.

* Corresponding author. Mailing address: Rega Institute for Medical Research, Minderbroedersstraat 10, B-3000 Leuven, Belgium. Phone: (32) 16 337341. Fax: (32) 16 337340. E-mail: jan.balzarini{at}rega.kuleuven.ac.be.

Journal of Virology, July 2001, p. 5772-5777, Vol. 75, No. 13
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.13.5772-5777.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • O'Neil, P. K., Sun, G., Yu, H., Ron, Y., Dougherty, J. P., Preston, B. D. (2002). Mutational Analysis of HIV-1 Long Terminal Repeats to Explore the Relative Contribution of Reverse Transcriptase and RNA Polymerase II to Viral Mutagenesis. J. Biol. Chem. 277: 38053-38061 [Abstract] [Full Text]  


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