The antiviral factor APOBEC3G enhances the recognition of HIV-infected primary T cells by natural killer cells

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Abstract

APOBEC3G (A3G) is an intrinsic antiviral factor that inhibits the replication of human immunodeficiency virus (HIV) by deaminating cytidine residues to uridine. This causes guanosine-to-adenosine hypermutation in the opposite strand and results in inactivation of the virus. HIV counteracts A3G through the activity of viral infectivity factor (Vif), which promotes degradation of A3G. We report that viral protein R (Vpr), which interacts with a uracil glycosylase, also counteracted A3G by diminishing the incorporation of uridine. However, this process resulted in activation of the DNA-damage–response pathway and the expression of natural killer (NK) cell–activating ligands. Our results show that pathogen-induced deamination of cytidine and the DNA-damage response to virus-mediated repair of the incorporation of uridine enhance the recognition of HIV-infected cells by NK cells.

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Figure 1: Expression of NKG2D ligands in HIV-infected cells.
Figure 2: Upregulation of A3G correlates with upregulation of NKG2D ligands.
Figure 3: Activation of the DNA-damage response in HIV-infected primary T cells.
Figure 4: HIV-infected T cells are resistant to recognition by NK cells unless an NKG2D ligand is overexpressed.
Figure 5: The effect of Vif on lysis by NK cells.
Figure 6: Vif and Vpr limit the incorporation of uridine into primary T cells.
Figure 7: Binding of UNG2 by Vpr induces the expression of NKG2D ligands.

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Acknowledgements

We thank the AIDS Research and Reference Reagent Program, Division of AIDS, National Institute of Allergy and Infectious Diseases, US National Institutes of Health; M. Gately (Hoffmann La Roche) for human recombinant interleukin 2; H. Zhang, Y. Zhou and R. Siliciano (Johns Hopkins University) for pNL4-3-ΔE-EGFP (11100); K. Strebel (National Institute of Allergy and Infectious Diseases, US National Institutes of Health) for A3G antiserum (ApoC17); M.H. Malim (King's College London) for monoclonal antibody 319 to HIV-1 Vif; BioMolecular Technologies for antiserum to HIV-1SF2 p24; and the University of Michigan Flow Cytometry core, Sequencing Core (US National Institutes of Health grant P30CAO46592) and Hybridoma Core (US National Institutes of Health grant P30AR048310) and the Center for Statistical Consultation for services. Supported by US National Institutes of Health (R01 AI051192; T32GM007863 and T32AI007413 to M.M.; and UL1RR024986 (National Center for Research Resources) to A.O.-N.), US National Science Foundation (DGE 0718128 to L.A.M.). The content is solely the responsibility of the authors and does not necessarily represent the official views of National Center for Research Resources or the US National Institutes of Health.

Author information

J.M.N. and K.L.C. designed the experiments and prepared the manuscript; J.M.N., M.M., L.A.M., A.O.-N., W.S. and E.C.-F. did experiments; and all authors read and edited the manuscript.

Correspondence to Kathleen L Collins.

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