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Viruses
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Host-Mediated Viral Mutations: APOBECs, ADARs, and Beyond
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Host-Mediated Viral Mutations: APOBECs, ADARs, and Beyond

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Human Virology and Viral Diseases".

Deadline for manuscript submissions: 1 September 2025 | Viewed by 2053

Special Issue Editor

Prof. Dr. Jaquelin P. Dudley

E-Mail Website
Guest Editor
Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, USA
Interests: APOBECs; cytidine deaminase; AID; viral antagonists; viral hypermutation; innate immunity; viral selection
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The apolipoprotein B mRNA-editing enzyme, catalytic polypeptide (APOBEC) family of enzymes is responsible for the deamination of cytosine in single-stranded RNA and DNA. In humans, this family includes 11 members, including APOBEC1, 2, 3A, 3B, 3C, 3D, 3F, 3G, 3H, 4, and activation-induced cytidine deaminase (AID). The functions of these enzymes range from epigenetic modifications of DNA, including removal of methylcytosine and 5-hydroxymethylcytosine, to mutagenesis of host and viral mRNAs. Current evidence suggests that both RNA and DNA viruses are mutagenized by APOBECs, leading to selection and altered pathogenicity. Although APOBECs are typically associated with the innate immune response to viral infections, AID is a primordial member of the family that controls affinity maturation of antibodies as well as effector functions by class switch recombination. Viral manipulation of APOBECs often is observed by enzyme relocalization or degradation, and APOBEC antagonists include both virally specified RNAs and proteins. Adenosine deaminases acting on RNA (ADARs) result in inosine substitutions (A-to-I editing) on double-stranded RNAs. Both APOBECs and ADARs are inducible by interferons and can function in both the cytosol and nucleus to affect both viral and cellular gene function. In addition, multiple viruses, including SARS CoV-2, have been shown to induce the host DNA damage response (DDR), resulting in genomic loss of integrity and inflammation. This issue will address new insights into APOBECs, ADARs, and host DDR for their impact on viral selection and the immune response.

Prof. Dr. Jaquelin P. Dudley
Guest Editor

Manuscript Submission Information

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Keywords

  • cytosine and adenosine deamination
  • methylcytosine
  • epigenetics
  • mutagenesis
  • cancer
  • APOBEC antagonists
  • ADAR
  • DNA damage response
  • innate immunity
  • adaptive immunity
  • virus selection

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Published Papers (3 papers)

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Research

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18 pages, 3239 KiB  
Article
Design and Characterization of Inhibitors of Cell-Mediated Degradation of APOBEC3G That Decrease HIV-1 Infectivity
by Aubrey M. Sawyer, Cristina C. Vaca, Neha Malik, Isabelle Clerc, Joshua Craft, Hannah Hudson, Gaël K. Scholtés, Gary E. Schiltz, Meejeon Roh, Chisu Song and Richard T. D’Aquila
Viruses 2025, 17(4), 514; https://doi.org/10.3390/v17040514 - 1 Apr 2025
Viewed by 329
Abstract
The cytoplasmic human Apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3 or A3) cytidine deaminases G and F (A3G and A3F) can block the spread of human immunodeficiency virus (HIV). HIV counteracts this cell-intrinsic defense through a viral protein called viral infectivity factor [...] Read more.
The cytoplasmic human Apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3 or A3) cytidine deaminases G and F (A3G and A3F) can block the spread of human immunodeficiency virus (HIV). HIV counteracts this cell-intrinsic defense through a viral protein called viral infectivity factor (Vif). Vif causes proteasomal degradation of A3G and A3F proteins (A3G/F) in HIV-producing cells to ensure infectivity of virions subsequently released from these cells. Here, we optimized a lead compound reported previously to boost cellular levels of A3G. The modified analogs designed, synthesized, and evaluated here inhibit cell-mediated post-translational degradation of A3G/F, whether Vif is present or not. This increases A3G/F incorporation into Vif-positive virions to decrease viral infectivity. The compounds and processes described here can facilitate the development of new anti-HIV therapeutics whose host-targeted effect may not be evaded by resistance-conferring mutations in HIV Vif. Full article
(This article belongs to the Special Issue Host-Mediated Viral Mutations: APOBECs, ADARs, and Beyond)
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43 pages, 12081 KiB  
Article
Coevolution of Lentiviral Vif with Host A3F and A3G: Insights from Computational Modelling and Ancestral Sequence Reconstruction
by David Nicolas Giuseppe Huebert, Atefeh Ghorbani, Shaw Yick Brian Lam and Mani Larijani
Viruses 2025, 17(3), 393; https://doi.org/10.3390/v17030393 - 10 Mar 2025
Viewed by 595
Abstract
The evolutionary arms race between host restriction factors and viral antagonists provides crucial insights into immune system evolution and viral adaptation. This study investigates the structural and evolutionary dynamics of the double-domain restriction factors A3F and A3G and their viral inhibitor, Vif, across [...] Read more.
The evolutionary arms race between host restriction factors and viral antagonists provides crucial insights into immune system evolution and viral adaptation. This study investigates the structural and evolutionary dynamics of the double-domain restriction factors A3F and A3G and their viral inhibitor, Vif, across diverse primate species. By constructing 3D structural homology models and integrating ancestral sequence reconstruction (ASR), we identified patterns of sequence diversity, structural conservation, and functional adaptation. Inactive CD1 (Catalytic Domain 1) domains displayed greater sequence diversity and more positive surface charges than active CD2 domains, aiding nucleotide chain binding and intersegmental transfer. Despite variability, the CD2 DNA-binding grooves remained structurally consistent with conserved residues maintaining critical functions. A3F and A3G diverged in loop 7’ interaction strategies, utilising distinct molecular interactions to facilitate their roles. Vif exhibited charge variation linked to host species, reflecting its coevolution with A3 proteins. These findings illuminate how structural adaptations and charge dynamics enable both restriction factors and their viral antagonists to adapt to selective pressures. Our results emphasize the importance of studying structural evolution in host–virus interactions, with implications for understanding immune defense mechanisms, zoonotic risks, and viral evolution. This work establishes a foundation for further exploration of restriction factor diversity and coevolution across species. Full article
(This article belongs to the Special Issue Host-Mediated Viral Mutations: APOBECs, ADARs, and Beyond)
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Review

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16 pages, 1975 KiB  
Review
APOBEC3 Proteins: From Antiviral Immunity to Oncogenic Drivers in HPV-Positive Cancers
by Eliza Pizarro Castilha, Rosalba Biondo, Kleber Paiva Trugilo, Giulia Mariane Fortunato, Timothy Robert Fenton and Karen Brajão de Oliveira
Viruses 2025, 17(3), 436; https://doi.org/10.3390/v17030436 - 18 Mar 2025
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Abstract
The human APOBEC superfamily consists of eleven cytidine deaminase enzymes. Among them, APOBEC3 enzymes play a dual role in antiviral immunity and cancer development. APOBEC3 enzymes, including APOBEC3A (A3A) and APOBEC3B (A3B), induce mutations in viral DNA, effectively inhibiting viral replication but also [...] Read more.
The human APOBEC superfamily consists of eleven cytidine deaminase enzymes. Among them, APOBEC3 enzymes play a dual role in antiviral immunity and cancer development. APOBEC3 enzymes, including APOBEC3A (A3A) and APOBEC3B (A3B), induce mutations in viral DNA, effectively inhibiting viral replication but also promoting somatic mutations in the host genome, contributing to cancer development. A3A and A3B are linked to mutational signatures in over 50% of human cancers, with A3A being a potent mutagen. A3B, one of the first APOBEC3 enzymes linked to carcinogenesis, plays a significant role in HPV-associated cancers by driving somatic mutagenesis and tumor progression. The A3A_B deletion polymorphism results in a hybrid A3A_B gene, leading to increased A3A expression and enhanced mutagenic potential. Such polymorphism has been linked to an elevated risk of certain cancers, particularly in populations where it is more prevalent. This review explores the molecular mechanisms of APOBEC3 proteins, highlighting their dual roles in antiviral defense and tumorigenesis. We also discuss the clinical implications of genetic variants, such as the A3A_B polymorphism, mainly in HPV infection and associated cancers, providing a comprehensive understanding of their contributions to both viral restriction and cancer development. Full article
(This article belongs to the Special Issue Host-Mediated Viral Mutations: APOBECs, ADARs, and Beyond)
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