Identification of CD164 as an essential entry receptor for divergent adeno-associated viruses

Xiujuan Zhang; Donovan Richart; Shane McFarlin; Fang Cheng; Soo Yeun Park; Anwen Zhang-Chen; Richenda McFarlane; Chuan Xiao; Ziying Yan; Jianming Qiu

doi:10.1073/pnas.2525865123

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Identification of CD164 as an essential entry receptor for divergent adeno-associated viruses

Journal article

Open access

Peer reviewed

Identification of CD164 as an essential entry receptor for divergent adeno-associated viruses

Xiujuan Zhang, Donovan Richart, Shane McFarlin, Fang Cheng, Soo Yeun Park, Anwen Zhang-Chen, Richenda McFarlane, Chuan Xiao, Ziying Yan and Jianming Qiu

Proceedings of the National Academy of Sciences - PNAS, Vol.123(10), e2525865123

03/10/2026

DOI: 10.1073/pnas.2525865123

PMID: 41785320

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Abstract

Recombinant adeno-associated viruses (rAAVs) are widely used for in vivo gene delivery. While KIAA0319L, known as AAV receptor (AAVR), is essential for the transduction of multiserotype AAVs, it is dispensable for AAV4-related (Clade G) AAVs. We conducted a genome-wide CRISPR/Cas9 screen and identified CD164, a type I transmembrane sialomucin, as an essential entry receptor for Clade G AAVs. Ablation of CD164 expression substantially impaired both entry and transduction of Clade G AAVs. CD164-targeting antibodies and soluble CD164 ectodomain effectively blocked transduction. AAV4 capsids colocalized with CD164 at the plasma membrane and in endosomal compartments. In vitro, CD164 interacted with AAV4 or AAVrh32.33 capsids at high affinity. Importantly, systemic administration of rAAV4 or rAAVrh32.33 in knockout (KO) mice resulted in nearly complete loss of transgene expression. These findings establish CD164 as an essential entry receptor for Clade G AAV vectors and uncover a distinct AAVR-independent mechanism of AAV tropism.

Animals

Antigens, CD - genetics

Antigens, CD - metabolism

Capsid - metabolism

CRISPR-Cas Systems

Dependovirus - genetics

Dependovirus - metabolism

Dependovirus - physiology

Genetic Vectors - genetics

HEK293 Cells

Humans

Mice

Mice, Knockout

Receptors, Cell Surface - genetics

Receptors, Cell Surface - metabolism

Receptors, Virus - genetics

Receptors, Virus - metabolism

Transduction, Genetic

Virus Internalization

Details

Title: Subtitle: Identification of CD164 as an essential entry receptor for divergent adeno-associated viruses
Creators: Xiujuan Zhang - Laboratory of Molecular Genetics
Donovan Richart - Laboratory of Molecular Genetics
Shane McFarlin - Laboratory of Molecular Genetics
Fang Cheng - Laboratory of Molecular Genetics
Soo Yeun Park - University of Alabama at Birmingham
Anwen Zhang-Chen - Incell Corporation (United States)
Richenda McFarlane - Incell Corporation (United States)
Chuan Xiao - The University of Texas at El Paso
Ziying Yan - University of Alabama at Birmingham
Jianming Qiu - University of Kansas Medical Center
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.123(10), e2525865123
DOI: 10.1073/pnas.2525865123
PMID: 41785320
NLM abbreviation: Proc Natl Acad Sci U S A
ISSN: 1091-6490
eISSN: 1091-6490
Publisher: NATL ACAD SCIENCES
Grant note: AH-2126-20220331 / Welch Foundation (The Welch Foundation) AI182645 / HHS | National Institutes of Health (NIH) YAN23G0 / Cystic Fibrosis Foundation (CFF) HL174593 / HHS | National Institutes of Health (NIH) AI180416 / HHS | National Institutes of Health (NIH) AI166293 / HHS | National Institutes of Health (NIH) GM129525 / HHS | National Institutes of Health (NIH)
Language: English
Date published: 03/10/2026
Academic Unit: Anatomy and Cell Biology
Record Identifier: 9985141899702771

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