Fidelity of HIV-1 reverse transcriptase
Abstract
The human immunodeficiency virus type 1 (HIV-1) shows extensive genetic variation and undergoes rapid evolution. The fidelity of purified HIV-1 reverse transcriptase was measured during DNA polymerization in vitro by means of three different assays. Reverse transcriptase from HIV-1 introduced base-substitution errors in DNA from the bacteriophage φX174 amber 3 at estimated frequencies of 1/2000 to 1/4000. Analyses of misincorporation rates opposite a single template adenine residue showed that HIV-1 reverse transcriptase catalyzed nucleotide mismatches with a specificity of A:C >> A:G > A:A. The high error rate of HIV-1 reverse transcriptase in vitro translates to approximately five to ten errors per HIV-1 genome per round of replication in vivo. This high error rate suggests that misincorporation by HIV-1 reverse transcriptase is, at least in part, responsible for the hypermutability of the AIDS virus. The specificity of misincorporation may provide a basis for the systematic construction of antiviral nucleosides.
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HIV-1 is more error-prone than HTLV and BLV because it replicates actively.
“making them error-prone, especially for actively replicating retroviruses such as HIV-1 compared to others, such as HTLV and BLV”
From Beyond reverse transcription: molecular mechanisms and emerging paradigms in retroviral replication (2026) · cites this paper as Preston et al. 1988
Retroviral RTs lack proofreading mechanisms such as 3′ exonuclease activity, making them error-prone.
“The low fidelity of RT is primarily because retroviral RTs lack proofreading mechanisms (such as 3′ exonuclease activity), making them error-prone, especially for actively replicating retroviruses such as HIV-1 compared to others, such as HTLV and BLV (Battula and Loeb 1976, Starcich et al. 1986, Preston et al. 1988, Ratner et al. 1991, Dube et al. 1993, Willems et al. 1993).”
From Beyond reverse transcription: molecular mechanisms and emerging paradigms in retroviral replication (2026) · cites this paper as Preston et al. 1988
Cites
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Crystal structure at 3.5 A resolution of HIV-1 reverse transcriptase complexed with an inhibitor
Kohlstaedt, L. A., Wang, J., Friedman, J. M., Rice, P. A., & Steitz, T. A. (1992) · Science · doi:10.1126/science.1377403 · Cited by 1,914 · see citing works
Biochemical Basis of DNA Replication Fidelity
Goodman, M. F., Creighton, S., Bloom, L. B., Petruska, J., & Kunkel, T. A. (1993) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.3109/10409239309086792 · Cited by 446 · see citing works
Temin, H. M. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.15.6900 · Cited by 309 · see citing works
Defective HIV-1 proviruses produce viral proteins
Imamichi, H., Smith, M., Adelsberger, J. W., Izumi, T., Scrimieri, F., Sherman, B. T., Rehm, C. A., Imamichi, T., Pau, A., Catalfamo, M., et al. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1917876117 · Cited by 251 · see citing works
Viral error catastrophe by mutagenic nucleosides
Anderson, J. P., Daifuku, R., & Loeb, L. A. (2004) · Annual Review of Microbiology · doi:10.1146/annurev.micro.58.030603.123649 · Cited by 221 · see citing works
Self-citationSomatic APP gene recombination in Alzheimer’s disease and normal neurons
Lee, M.-H., Siddoway, B., Kaeser, G. E., Segota, I., Rivera, R., Romanow, W. J., Liu, C. S., Park, C., Kennedy, G., Long, T., et al. (2018) · Nature · doi:10.1038/s41586-018-0718-6 · Cited by 210 · see citing works
Fidelity of HIV-1 reverse transcriptase copying RNA in vitro
Ji, J., & Loeb, L. A. (1992) · Biochemistry · doi:10.1021/bi00119a002 · Cited by 208 · see citing works
Self-citationBeyond reverse transcription: molecular mechanisms and emerging paradigms in retroviral replication
Jehad, M. A., Ali, L. M., Pillai, V. N., Prabhu, S. G., Mustafa, F., & Rizvi, T. A. (2026) · FEMS Microbiology Reviews · doi:10.1093/femsre/fuaf066 · Cited by 5 · see citing works
“…(such as 3 exonuclease activity), making them error-prone, especially for actively replicating retro-viruses such as HIV-1 compared to others, such as HTLV and BLV (Battula and Loeb 1976 , Starcich et al. 1986 , Preston et al. 1988 , Rat-ner et al. 1991 , Dube et al. 1993 , Willems et al. 1993 ).”
- Authors
- Preston, B. D., Poiesz, B. J., & Loeb, L. A.
- Affiliations
- University of Washington (US)
- SUNY Upstate Medical University (US)
- Venue
- Science
- Published
- 1988-11-25
- Volume
- 242
- Issue
- 4882
- Pages
- 1168-1171
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2090126383
- Cited by
- 931
- References
- 1
- Citations by year
- 2026: 9 · 2025: 11 · 2024: 9 · 2023: 11 · 2022: 15 · 2021: 7 · 2020: 12 · 2019: 17 · 2018: 11 · 2017: 19 · 2016: 14 · 2015: 24 · 2014: 20 · 2013: 35 · 2012: 42
- FWCI
- 35.14
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (n01ai072654-005, 5r35ca039903-14)
- National Cancer Institute (CA-07263-03, R 35-CA-39903)
- National Institute of Allergy and Infectious Diseases (N01AI72654)
- Topics
- Health Sciences › Medicine › Infectious Diseases › HIV/AIDS drug development and treatment
- Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Keywords
- HIV-1 reverse transcriptase, error rate, nucleotide mismatch
- MeSH terms
- DNA, DNA Polymerase II, DNA, Viral, Electrophoresis, Polyacrylamide Gel, HIV, Kinetics, Moloney murine leukemia virus, Mutation, Avian Myeloblastosis Virus, Nucleotides, Bacteriophage phi X 174, RNA-Directed DNA Polymerase
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