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Journal of Virology, October 2000, p. 9525-9531, Vol. 74, No. 20
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

In Vivo Analysis of Human T-Cell Leukemia Virus Type 1 Reverse Transcription Accuracy

Louis M. Mansky*

Department of Molecular Virology, Immunology, and Medical Genetics, Center for Retrovirus Research, The Arthur James Cancer Hospital and Solove Research Institute, and Comprehensive Cancer Center, Ohio State University Medical Center, Columbus, Ohio 43210

Received 11 May 2000/Accepted 17 July 2000

Several studies have indicated that the genetic diversity of human T-cell leukemia virus type 1 (HTLV-1), a virus associated with adult T-cell leukemia, is significantly lower than that of other retroviruses, including that of human immunodeficiency virus type 1 (HIV-1). To test whether HTLV-1 variation is lower than other retroviruses, a tractable vector system has been developed to measure reverse transcription accuracy in one round of HTLV-1 replication. This system consists of a HTLV-1 vector that contains a cassette with the neomycin phosphotransferase (neo) gene, a bacterial origin of DNA replication, and the lacZalpha peptide gene region (the mutational target). The vector was replicated by trans-complementation with helper plasmids. The in vivo mutation rate for HTLV-1 was determined to be 7 × 10-6 mutations per target base pair per replication cycle. The majority of the mutations identified were base substitution mutations, namely, G-to-A and C-to-T transitions, frameshift mutations, and deletion mutations. Mutation of the methionine residue in the conserved YMDD motif of the HTLV-1 reverse transcriptase to either alanine or valine (i.e., M188A or M188V) led to a factor of two increase in the rate of mutation, indicating the role of this motif in enzyme accuracy. The HTLV-1 in vivo mutation rate is comparable to that of bovine leukemia virus (BLV), another member of the HTLV/BLV genus of retroviruses, and is about fourfold lower than that of HIV-1. These observations indicate that while the mutation rate of HTLV-1 is significantly lower than HIV-1, this lower rate alone would not explain the low diversity in HTLV-1 isolates, supporting the hypothesis that HTLV-1 replicates primarily as a provirus during cellular DNA replication rather than as a virus via reverse transcription.

* Mailing address: Department of Molecular Virology, Immunology, and Medical Genetics, 2078 Graves Hall, 333 W. 10th Ave., Columbus, OH 43210. Phone: (614) 292-5525. Fax: (614) 292-9805. E-mail: mansky.3{at}osu.edu.

Journal of Virology, October 2000, p. 9525-9531, Vol. 74, No. 20
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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