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Journal of Virology, January 2009, p. 295-303, Vol. 83, No. 1
0022-538X/09/$08.00+0     doi:10.1128/JVI.01665-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Polymorphisms and Splice Variants Influence the Antiretroviral Activity of Human APOBEC3H{triangledown}

Ariana Harari,{dagger} Marcel Ooms,{dagger} Lubbertus C. F. Mulder, and Viviana Simon*

Departments of Medicine and Microbiology, Emerging Pathogens Institute, Mount Sinai School of Medicine, New York, New York 10029

Received 5 August 2008/ Accepted 8 October 2008

Human APOBEC3H belongs to the APOBEC3 family of cytidine deaminases that potently inhibit exogenous and endogenous retroviruses. The impact of single nucleotide polymorphisms (SNP) and alternative splicing on the antiretroviral activity of human APOBEC3H is currently unknown. In this study, we show that APOBEC3H transcripts derived from human peripheral blood mononuclear cells are polymorphic in sequence and subject to alternative splicing. We found that APOBEC3H variants encoding a SNP cluster (G105R, K121D and E178D, hapII-RDD) restricted human immunodeficiency virus type 1 (HIV-1) more efficiently than wild-type APOBEC3H (hapI-GKE). All APOBEC3H variants tested were resistant to HIV-1 Vif, the viral protein that efficiently counteracts APOBEC3G/3F activity. Alternative splicing of APOBEC3H was common and resulted in variants with distinct C-terminal regions and variable antiretroviral activities. Splice variants of hapI-GKE displayed a wide range of antiviral activities, whereas similar splicing events in hapII-RDD resulted in proteins that uniformly and efficiently restricted viral infectivity (>20-fold). Site-directed mutagenesis identified G105R in hapI-GKE and D121K in hapII-RDD as critical substitutions leading to an average additional 10-fold increase in antiviral activity. APOBEC3H variants were catalytically active and, similarly to APOBEC3F, favored a GA dinucleotide context. HIV-1 mutagenesis as a mode of action for APOBEC3H is suggested by the decrease of restriction observed with a cytidine deaminase domain mutant and the inverse correlation between G-to-A mutations and infectivity. Thus, the anti-HIV activity of APOBEC3H seems to be regulated by a combination of genomic variation and alternative splicing. Since prevalence of hapII-RDD is high in populations of African descent, these findings raise the possibility that some individuals may harbor effective as well as HIV-1 Vif-resistant intracellular antiviral defense mechanisms.

* Corresponding author. Mailing address: Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1090, New York City, NY 10029. Phone: (212) 241-8388. Fax: (212) 849-2643. E-mail: viviana.simon{at}mssm.edu

{triangledown} Published ahead of print on 22 October 2008.

{dagger} A.H. and M.O. contributed equally.

Journal of Virology, January 2009, p. 295-303, Vol. 83, No. 1
0022-538X/09/$08.00+0     doi:10.1128/JVI.01665-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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