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The cytidine deaminase CEM15 induces hypermutation in newly synthesized HIV-1 DNA

Abstract

High mutation frequency during reverse transcription has a principal role in the genetic variation of primate lentiviral populations. It is the main driving force for the generation of drug resistance and the escape from immune surveillance. G to A hypermutation is one of the characteristics of primate lentiviruses, as well as other retroviruses, during replication in vivo and in cell culture1,2,3,4,5,6. The molecular mechanisms of this process, however, remain to be clarified. Here, we demonstrate that CEM15 (also known as apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3G; APOBEC3G)7,8, an endogenous inhibitor of human immunodeficiency virus type 1 (HIV-1) replication, is a cytidine deaminase and is able to induce G to A hypermutation in newly synthesized viral DNA. This effect can be counteracted by the HIV-1 virion infectivity factor (Vif). It seems that this viral DNA mutator is a viral defence mechanism in host cells that may induce either lethal hypermutation or instability of the incoming nascent viral reverse transcripts, which could account for the Vif-defective phenotype. Importantly, the accumulation of CEM15-mediated non-lethal hypermutation in the replicating viral genome could potently contribute to the genetic variation of primate lentiviral populations.

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Figure 1: G to A hypermutation in viral DNA of Δvif viruses from non-permissive cells or semi-permissive cells.
Figure 2: G to A hypermutation in newly synthesized DNA of viruses generated from cells containing CEM15.
Figure 3: CEM15 has cytidine deaminase activity in vitro.
Figure 4: CEM15 without cytidine deaminase activity can neither inhibit the infectivity nor induce hypermutation in the newly synthesized DNA of Δvif viruses. pNL4-3 or pNL4-3Δvif were transfected into 293T cells with CEM15 or CEM15 mutants.

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Acknowledgements

This work was supported by research grants from the National Institute of Health (H.Z).

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Zhang, H., Yang, B., Pomerantz, R. et al. The cytidine deaminase CEM15 induces hypermutation in newly synthesized HIV-1 DNA. Nature 424, 94–98 (2003). https://doi.org/10.1038/nature01707

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