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Journal of Virology, December 2008, p. 11889-11901, Vol. 82, No. 23
0022-538X/08/$08.00+0     doi:10.1128/JVI.01537-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Equine Infectious Anemia Virus Resists the Antiretroviral Activity of Equine APOBEC3 Proteins through a Packaging-Independent Mechanism{triangledown}

Hal P. Bogerd,1 Rebecca L. Tallmadge,2 J. Lindsay Oaks,2 Susan Carpenter,2 and Bryan R. Cullen1*

Department of Molecular Genetics and Microbiology and Center for Virology, Duke University Medical Center, Durham, North Carolina 27710,1 Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, Washington 991642

Received 21 July 2008/ Accepted 19 September 2008

Equine infectious anemia virus (EIAV), uniquely among lentiviruses, does not encode a vif gene product. Other lentiviruses, including human immunodeficiency virus type 1 (HIV-1), use Vif to neutralize members of the APOBEC3 (A3) family of intrinsic immunity factors that would otherwise inhibit viral infectivity. This suggests either that equine cells infected by EIAV in vivo do not express active A3 proteins or that EIAV has developed a novel mechanism to avoid inhibition by equine A3 (eA3). Here, we demonstrate that horses encode six distinct A3 proteins, four of which contain a single copy of the cytidine deaminase (CDA) consensus active site and two of which contain two CDA motifs. This represents a level of complexity previously seen only in primates. Phylogenetic analysis of equine single-CDA A3 proteins revealed two proteins related to human A3A (hA3A), one related to hA3C, and one related to hA3H. Both equine double-CDA proteins are similar to hA3F and were named eA3F1 and eA3F2. Analysis of eA3F1 and eA3F2 expression in vivo shows that the mRNAs encoding these proteins are widely expressed, including in cells that are natural EIAV targets. Both eA3F1 and eA3F2 inhibit retrotransposon mobility, while eA3F1 is a potent inhibitor of a Vif-deficient HIV-1 mutant and induces extensive editing of HIV-1 reverse transcripts. However, both eA3F1 and eA3F2 are weak inhibitors of EIAV. Surprisingly, eA3F1 and eA3F2 were packaged into EIAV and HIV-1 virions as effectively as hA3G, although only the latter inhibited EIAV infectivity. Moreover, all three proteins bound both the HIV-1 and EIAV nucleocapsid protein specifically in vitro. It therefore appears that EIAV has evolved a novel mechanism to specifically neutralize the biological activities of the cognate eA3F1 and eA3F2 proteins at a step subsequent to virion incorporation.

* Corresponding author. Mailing address: Duke University Medical Center, Room 426, CARL Building, P.O. Box 3025, Durham, NC 27710. Phone: (919) 684-3369. Fax: (919) 681-8979. E-mail: bryan.cullen{at}duke.edu

{triangledown} Published ahead of print on 25 September 2008.

Journal of Virology, December 2008, p. 11889-11901, Vol. 82, No. 23
0022-538X/08/$08.00+0     doi:10.1128/JVI.01537-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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