A viral APOBEC3 antagonist distinguishes HHV-6A from HHV-6B

Human herpesviruses exhibit diverse pathogenic outcomes and the molecular reasons are not fully understood. Human herpesvirus 6B (HHV-6B) causes exanthema subitum and encephalitis, whereas the closely related HHV-6A is typically asymptomatic. Here, we show that cellular APOBEC3 enzymes restrict HHV-6A replication but not HHV-6B. HHV-6B expresses higher levels of the U28 protein, which binds multiple APOBEC3 proteins and promotes their relocalization and degradation. In contrast, HHV-6A fails to counteract APOBEC3 activity and accumulates extensive mutations in both cell- and patient-derived viral genomes. Individual APOBEC3 gene ablation enhances HHV-6A replication and reduces the viral mutation burden. Together, our studies suggest that differential susceptibility to APOBEC3 restriction may help to shape the evolvability and clinical manifestations of HHV-6A and HHV-6B.

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Publication Details

Journal
Nature Communications
Published
2026-05-01
DOI
https://doi.org/10.1038/s41467-026-71951-6
Primary Topic
Cytomegalovirus and herpesvirus research
Type
article
Field-Weighted Citation Impact
0.00

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article

A viral APOBEC3 antagonist distinguishes HHV-6A from HHV-6B

Bochao Wang, Satoshi Nagamata, Mitsuhiro Nishimura, Yoshiki Kawamura et al.
Nature Communications
Cytomegalovirus and herpesvirus research
article

A viral APOBEC3 antagonist distinguishes HHV-6A from HHV-6B

Bochao Wang, Satoshi Nagamata, Mitsuhiro Nishimura, Yoshiki Kawamura, Reuben S. Harris, Jun Arii, Salma Aktar, Jing Rin Huang, Mansaku Hirai, Tetsushi Yoshikawa, Hiroki Miura, Yasuko Mori
article en

Abstract

Human herpesviruses exhibit diverse pathogenic outcomes and the molecular reasons are not fully understood. Human herpesvirus 6B (HHV-6B) causes exanthema subitum and encephalitis, whereas the closely related HHV-6A is typically asymptomatic. Here, we show that cellular APOBEC3 enzymes restrict HHV-6A replication but not HHV-6B. HHV-6B expresses higher levels of the U28 protein, which binds multiple APOBEC3 proteins and promotes their relocalization and degradation. In contrast, HHV-6A fails to counteract APOBEC3 activity and accumulates extensive mutations in both cell- and patient-derived viral genomes. Individual APOBEC3 gene ablation enhances HHV-6A replication and reduces the viral mutation burden. Together, our studies suggest that differential susceptibility to APOBEC3 restriction may help to shape the evolvability and clinical manifestations of HHV-6A and HHV-6B.

Nature CommunicationsVol. 17(1)
Hiroshima University (JP), Howard Hughes Medical Institute (US), Fujita Health University (JP), Fujita Health University Okazaki Medical Center, The University of Texas at San Antonio (US), Kobe University (JP)
Takeda Science Foundation, Japan Agency for Medical Research and Development, Ministry of Education, Culture, Sports, Science and Technology, Waksman Foundation of Japan, Japan Society for the Promotion of Science, Japan Science and Technology Agency, National Institute of Allergy and Infectious Diseases
Openalex Percentile: Top 14%
Cytomegalovirus and herpesvirus research
DOIOpen Access PDFOpenAlex
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