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Journal of Virology, September 2008, p. 8743-8761, Vol. 82, No. 17
0022-538X/08/$08.00+0     doi:10.1128/JVI.00584-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Conserved Footprints of APOBEC3G on Hypermutated Human Immunodeficiency Virus Type 1 and Human Endogenous Retrovirus HERV-K(HML2) Sequences{triangledown} ,{dagger}

Andrew E. Armitage,1 Aris Katzourakis,2 Tulio de Oliveira,2,5 John J. Welch,4 Robert Belshaw,2 Kate N. Bishop,3 Beatrice Kramer,3 Andrew J. McMichael,1 Andrew Rambaut,4 and Astrid K. N. Iversen1*

MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom,1 Department of Zoology, University of Oxford, South Parks Road, Oxford OX1 3PS, United Kingdom,2 Department of Infectious Diseases, King's College London School of Medicine, London SE1 9RT, United Kingdom,3 Institute of Evolutionary Biology, University of Edinburgh, Edinburgh EH9 3JT, United Kingdom,4 MRC Bioinformatics Capacity Development Research Unit, South African National Bioinformatics Institute, University of the Western Cape, Cape Town, South Africa5

Received 14 March 2008/ Accepted 11 June 2008

The human polynucleotide cytidine deaminases APOBEC3G (hA3G) and APOBEC3F (hA3F) are antiviral restriction factors capable of inducing extensive plus-strand guanine-to-adenine (G-to-A) hypermutation in a variety of retroviruses and retroelements, including human immunodeficiency virus type 1 (HIV-1). They differ in target specificity, favoring plus-strand 5'GG and 5'GA dinucleotide motifs, respectively. To characterize their mutational preferences in detail, we analyzed single-copy, near-full-length HIV-1 proviruses which had been hypermutated in vitro by hA3G or hA3F. hA3-induced G-to-A mutation rates were significantly influenced by the wider sequence context of the target G. Moreover, hA3G, and to a lesser extent hA3F, displayed clear tetranucleotide preference hierarchies, irrespective of the genomic region examined and overall hypermutation rate. We similarly analyzed patient-derived hypermutated HIV-1 genomes using a new method for estimating reference sequences. The majority of these, regardless of subtype, carried signatures of hypermutation that strongly correlated with those induced in vitro by hA3G. Analysis of genome-wide hA3-induced mutational profiles confirmed that hypermutation levels were reduced downstream of the polypurine tracts. Additionally, while hA3G mutations were found throughout the genome, hA3F often intensely mutated shorter regions, the locations of which varied between proviruses. We extended our analysis to human endogenous retroviruses (HERVs) from the HERV-K(HML2) family, finding two elements that carried clear footprints of hA3G activity. This constitutes the most direct evidence to date for hA3G activity in the context of natural HERV infections, demonstrating the involvement of this restriction factor in defense against retroviral attacks over millions of years of human evolution.

* Corresponding author. Mailing address: MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DS, United Kingdom. Phone: 44 (0) 1865 222498. Fax: 44 (0) 1865 222502. E-mail: aiversen{at}hammer.imm.ox.ac.uk

{triangledown} Published ahead of print on 18 June 2008.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

Journal of Virology, September 2008, p. 8743-8761, Vol. 82, No. 17
0022-538X/08/$08.00+0     doi:10.1128/JVI.00584-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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  • Petit, V., Vartanian, J.-P., Wain-Hobson, S. (2009). Powerful mutators lurking in the genome. Phil Trans R Soc B 364: 705-715 [Abstract] [Full Text]  


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