Capsid-mediated control of adeno-associated viral transcription determines host range
Ezra J. Loeb,
Patrick L. Havlik,
Zachary C. Elmore,
Alan Rosales,
Sophia M. Fergione,
Trevor J. Gonzalez,
Timothy J. Smith,
Abigail R. Benkert,
David N. Fiflis,
Aravind Asokan
Affiliations
Ezra J. Loeb
Department of Biomedical Engineering, Duke University, Durham, NC, USA
Patrick L. Havlik
Department of Surgery, Duke University School of Medicine, Durham, NC, USA
Zachary C. Elmore
Department of Surgery, Duke University School of Medicine, Durham, NC, USA
Alan Rosales
Department of Biomedical Engineering, Duke University, Durham, NC, USA
Sophia M. Fergione
Department of Surgery, Duke University School of Medicine, Durham, NC, USA
Trevor J. Gonzalez
Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, USA
Timothy J. Smith
Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, USA
Abigail R. Benkert
Department of Surgery, Duke University School of Medicine, Durham, NC, USA
David N. Fiflis
Department of Biomedical Engineering, Duke University, Durham, NC, USA
Aravind Asokan
Department of Biomedical Engineering, Duke University, Durham, NC, USA; Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, USA; Department of Surgery, Duke University School of Medicine, Durham, NC, USA; Corresponding author
Summary: Adeno-associated virus (AAV) is a member of the genus Dependoparvovirus, which infects a wide range of vertebrate species. Here, we observe that, unlike most primate AAV isolates, avian AAV is transcriptionally silenced in human cells. By swapping the VP1 N terminus from primate AAVs (e.g., AAV8) onto non-mammalian isolates (e.g., avian AAV), we identify a minimal component of the AAV capsid that controls viral transcription and unlocks robust transduction in both human cells and mouse tissue. This effect is accompanied by increased AAV genome chromatin accessibility and altered histone methylation. Proximity ligation analysis reveals that host factors are selectively recruited by the VP1 N terminus of AAV8 but not avian AAV. Notably, these include AAV essential factors implicated in the nuclear factor κB pathway, chromatin condensation, and histone methylation. We postulate that the AAV capsid has evolved mechanisms to recruit host factors to its genome, allowing transcriptional activation in a species-specific manner.
