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Journal of Virology, March 2004, p. 2426-2433, Vol. 78, No. 5
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.5.2426-2433.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Unselected Mutations in the Human Immunodeficiency Virus Type 1 Genome Are Mostly Nonsynonymous and Often Deleterious

Feng Gao,^1* Yalu Chen,² David N. Levy,² Joan A. Conway,² Thomas B. Kepler,³ and Huxiong Hui²

Department of Medicine, Duke University Medical Center,¹ Department of Biostatistics and Bioinformatics and Center for Bioinformatics and Computational Biology, Institute for Genome Sciences and Policy, Duke University, Durham, North Carolina 27710,³ Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294²

Received 1 April 2003/ Accepted 8 November 2003

Mutation rates of human immunodeficiency virus type 1 (HIV-1) genomes have been estimated using purified reverse transcriptase or single-round infection system. Since small sequences were used as templates, the overall mutation rates could only be extrapolated and the biological significance of mutations is unknown. For direct estimation of HIV-1 mutation rates and understanding of the potential biological influences of mutations, we obtained 19 complete or nearly full-length proviral genomes from single-round-infected adherent cells of lymphocytes by using a lambda phage library method and a long-range PCR technique. Analysis of 160,000 bp of sequences showed that the overall mutation rate of HIV-1 genomes was 5.4 x 10^-5 per base per replication cycle. On average, 1.1 mutations (range, 0 to 3) were generated in each viral genome during one infection cycle. Inspection of the mutations in the HIV-1 genome revealed that all site mutations within protein-coding regions were nonsynonymous mutations. Among all mutations, half were deleterious (premature stop codon and deletions) and would result in defective genomes. By applying the same system to an HIV-1 genome with a G262A mutation in the thumb region of the reverse transcriptase, a significant increase was observed in deletion and insertion mutation rates but no increase in the overall mutation rate in viral genomes was found.

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* Corresponding author. Mailing address: Department of Medicine, Duke University Medical Center, 112 Research Park III, Research Dr., Box 3347, DUMC, Durham, NC 27710. Phone: (919) 668-6433. Fax: (919) 668-6435. E-mail: fgao{at}duke.edu.

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Journal of Virology, March 2004, p. 2426-2433, Vol. 78, No. 5
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.5.2426-2433.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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