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Published as doi: 10.1096/fj.06-6773com.
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(The FASEB Journal. 2007;21:217-222.)
© 2007 FASEB

Zinc chelation inhibits HIV Vif activity and liberates antiviral function of the cytidine deaminase APOBEC3G

Zuoxiang Xiao*,{dagger}, Elana Ehrlich*, Kun Luo*,{dagger}, Yong Xiong* and Xiao-Fang Yu*,{dagger},1

* Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA; and

{dagger} Second Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, China

1Correspondence: Department of Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe St., Baltimore, MD 21205, USA. E-mail: xfyu{at}jhsph.edu

APOBEC3 proteins are cellular antiviral proteins that are targeted for proteasomal degradation by primate lentiviral Vif proteins. Vif acts as a substrate receptor for the Cullin5 (Cul5) E3 ubiquitin ligase, specifically interacting with Cul5 through a novel H-x5-C-x17–18-C-x3–5-H zinc binding motif. Using the membrane-permeable zinc chelator, N,N,N',N'-tetrakis-(2-pyridylmethyl) ethylenediamine (TPEN), we demonstrated a requirement for zinc for Vif function in vivo. Treatment with TPEN at an IC50 of 1.79 µM inhibits Cul5 recruitment and APOBEC3G (A3G) degradation. Zinc chelation prevented Vif function in infectivity assays, allowing the virus to become sensitive to the antiviral activity of A3G. Zinc chelation had no effect on cellular Cul5-SOCS3 E3 ligase assembly, suggesting that zinc-dependent E3 ligase assembly may be unique to HIV-1 Vif, representing a new target for novel drug design.—Xiao, X., Ehrlich, E., Luo, K., Xiong, Y., Yu, X-F. Zinc chelation inhibits HIV Vif activity and liberates antiviral function of the cytidine deaminase APOBEC3G.


Key Words: HIV-1 virion • lentiviral Vif proteins • TPEN • zinc binding motif




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