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Journal of Virology, September 2006, p. 9259-9269, Vol. 80, No. 18
0022-538X/06/$08.00+0     doi:10.1128/JVI.00888-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Population Level Analysis of Human Immunodeficiency Virus Type 1 Hypermutation and Its Relationship with APOBEC3G and vif Genetic Variation{dagger}

Craig Pace,1 Jean Keller,1 David Nolan,1 Ian James,1 Silvana Gaudieri,1,2 Corey Moore,1 and Simon Mallal1,3*

Centre for Clinical Immunology & Biomedical Statistics, Royal Perth Hospital & Murdoch University, GPO Box X2213, Perth 6847, Australia,1 Centre for Forensic Science, School of Anatomy & Human Biology, University of Western Australia, Nedlands, Australia,2 Department of Clinical Immunology & Biochemical Genetics, Royal Perth Hospital, Wellington St., Perth 6000, Australia3

Received 2 May 2006/ Accepted 14 June 2006

APOBEC3G and APOBEC3F restrict human immunodeficiency virus type 1 (HIV-1) replication in vitro through the induction of G->A hypermutation; however, the relevance of this host antiviral strategy to clinical HIV-1 is currently not known. Here, we describe a population level analysis of HIV-1 hypermutation in near-full-length clade B proviral DNA sequences (n = 127). G->A hypermutation conforming to expected APOBEC3G polynucleotide sequence preferences was inferred in 9.4% (n = 12) of the HIV-1 sequences, with a further 2.4% (n = 3) conforming to APOBEC3F, and was independently associated with reduced pretreatment viremia (reduction of 0.7 log10 copies/ml; P = 0.001). Defective vif was strongly associated with HIV-1 hypermutation, with additional evidence for a contribution of vif amino acid polymorphism at residues important for APOBEC3G-vif interactions. A concurrent analysis of APOBEC3G polymorphism revealed this gene to be highly conserved at the amino acid level, although an intronic allele (6,892 C) was marginally associated with HIV-1 hypermutation. These data indicate that APOBEC3G-induced HIV-1 hypermutation represents a potent host antiviral factor in vivo and that the APOBEC3G-vif interaction may represent a valuable therapeutic target.

* Corresponding author. Mailing address: Centre for Clinical Immunology and Biomedical Statistics, 2nd Floor, North Block, Royal Perth Hospital, Wellington Street, Perth 6000, Western Australia. Phone: 61 89 224 2899. Fax: 61 89 224 2920. E-mail: s.mallal{at}murdoch.edu.au.

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

Journal of Virology, September 2006, p. 9259-9269, Vol. 80, No. 18
0022-538X/06/$08.00+0     doi:10.1128/JVI.00888-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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