Abstract
The APOBEC family of DNA cytosine deaminases provides a broad and overlapping defense against viral infections. Successful viral pathogens, by definition, have evolved strategies to escape restriction by the APOBEC enzymes of their hosts. HIV-1 and related retroviruses are thought to be the predominant natural substrates of APOBEC enzymes due to obligate single-stranded DNA replication intermediates, abundant evidence for cDNA strand C-to-U editing (genomic strand G-to-A hypermutation), and a potent APOBEC degradation mechanism. In contrast, much lower mutation rates are observed in double-stranded DNA herpesviruses and the evidence for APOBEC mutation has been less compelling. However, recent work has revealed that Epstein-Barr virus (EBV), Kaposi's sarcoma herpesvirus (KSHV), and herpes simplex virus-1 (HSV-1) are potential substrates for cellular APOBEC enzymes. To prevent APOBEC-mediated restriction these viruses have repurposed their ribonucleotide reductase (RNR) large subunits to directly bind, inhibit, and relocalize at least two distinct APOBEC enzymes - APOBEC3B and APOBEC3A. The importance of this interaction is evidenced by genetic inactivation of the EBV RNR (BORF2), which results in lower viral infectivity and higher levels of C/G-to-T/A hypermutation. This RNR-mediated mechanism therefore likely functions to protect lytic phase viral DNA replication intermediates from APOBEC-catalyzed DNA C-to-U deamination. The RNR-APOBEC interaction defines a new host-pathogen conflict that the virus must win in real-time for transmission and pathogenesis. However, partial losses over evolutionary time may also benefit the virus by providing mutational fuel for adaptation.
Original language | English (US) |
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Article number | 390 |
Journal | Viruses |
Volume | 13 |
Issue number | 3 |
DOIs | |
State | Published - Feb 28 2021 |
Bibliographical note
Publisher Copyright:© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
Keywords
- APOBEC
- DNA cytosine deamination
- DNA editing
- Evolution
- Herpesvirus
- Innate antiviral immunity
- Mutation
- Restriction factors
- Ribonucleotide reductase
- APOBEC Deaminases/genetics
- Humans
- DNA, Viral/genetics
- Herpesviridae Infections/genetics
- DNA Replication/genetics
- Virus Replication/genetics
- Animals
- DNA Viruses/genetics
- Host-Pathogen Interactions/genetics
- Herpesviridae/genetics
PubMed: MeSH publication types
- Review
- Research Support, Non-U.S. Gov't
- Journal Article
- Research Support, N.I.H., Extramural