AAV Receptor Insights: Biological Role and Disease Links

Adeno-associated virus (AAV) receptors are critical for viral entry into host cells, influencing gene therapy and potential disease mechanisms. Understanding these receptors can improve AAV-based treatments and reveal broader biological functions.

Recent research has shed light on how these receptors interact with AAV, their structure, and their distribution across tissues. These findings have implications for targeted therapies and potential disease links.

Biological Significance Of The AAV Receptor

The adeno-associated virus receptor (AAVR), identified as KIAA0319L, is a transmembrane protein that facilitates viral attachment and internalization, directly affecting AAV-based gene delivery. Beyond viral infection, AAVR plays a role in cellular trafficking and membrane dynamics, which are essential for maintaining cellular function. Its ability to mediate endocytosis and intracellular transport highlights its importance in both normal physiology and therapeutic applications.

AAVR is particularly significant in gene therapy, where AAV vectors deliver genetic material for inherited disorders. Its role in determining tissue tropism—how selectively AAV infects different cell types—affects treatment success. Variations in AAVR expression across tissues influence gene transfer efficiency. High expression in the liver and central nervous system aligns with the success of AAV-based therapies for conditions like spinal muscular atrophy and hemophilia. Understanding these patterns helps refine vector design to enhance specificity and reduce off-target effects.

Beyond viral entry, AAVR is involved in protein trafficking and receptor recycling. It interacts with endosomal and lysosomal pathways, suggesting a role in intracellular sorting. This function is particularly relevant in neurobiology, where disruptions in protein trafficking are linked to neurodegenerative diseases. The potential influence of AAV-based therapies on these pathways requires further investigation into long-term effects.

Structure And Binding Mechanism

AAVR is a type I transmembrane protein with multiple polycystic kidney disease (PKD) domains in its extracellular region, which serve as key contact points for AAV binding. Structural studies using cryo-electron microscopy and X-ray crystallography have shown that PKD2 and PKD3 undergo conformational shifts upon viral attachment, enabling stable docking. Even minor mutations in these regions can impair AAV binding and reduce transduction efficiency in gene therapy.

AAVR’s flexible structure allows it to accommodate various AAV serotypes, with different capsid proteins exhibiting distinct affinities for specific PKD domains. AAV2 primarily interacts with PKD2, while AAV5 shows preference for PKD1. This variability influences tropism and transduction efficiency across cell types. Additionally, glycosylation patterns on AAVR’s extracellular domain modulate viral affinity, highlighting the role of post-translational modifications in receptor-virus interactions.

Following binding, AAVR facilitates viral uptake through endocytic trafficking. Its intracellular domain interacts with cytoskeletal elements and vesicular transport proteins, guiding AAV into the endosomal compartment. pH-dependent conformational changes within the endosome promote viral release from AAVR, allowing nuclear entry. Studies using receptor knockdown models show that AAV transduction efficiency drops significantly in the absence of functional AAVR, reinforcing its essential role in the viral life cycle.

Tissue Distribution And Variants

AAVR expression varies across tissues, affecting viral tropism and gene therapy outcomes. High levels are found in the liver, central nervous system, and skeletal muscle, aligning with the success of AAV-based treatments targeting these organs. Hepatic expression supports systemic gene therapy for conditions like hemophilia, while strong neuronal presence facilitates treatments for spinal muscular atrophy.

However, variability exists even within the same tissue. Single-cell RNA sequencing has revealed differential AAVR expression among hepatocytes, with some subpopulations displaying higher receptor density. This heterogeneity affects gene therapy outcomes, as regions with lower receptor availability may exhibit reduced transduction efficiency. In skeletal muscle, differences in AAVR levels between fiber types complicate vector targeting, requiring capsid modifications to enhance uptake in less permissive cells.

Genetic variants of AAVR also influence viral susceptibility and therapeutic outcomes. Polymorphisms in KIAA0319L have been linked to altered receptor function. Some mutations produce truncated or misfolded proteins that fail to support efficient viral entry, potentially explaining poor transduction in clinical trials. Conversely, certain variants may enhance receptor affinity for AAV capsids, leading to unexpectedly high transduction rates in some individuals. Screening for AAVR variants could help predict patient-specific responses and guide vector selection.

Methods Used To Identify And Study This Receptor

The identification and characterization of AAVR have relied on molecular biology, structural analysis, and functional assays. Genome-wide CRISPR-Cas9 screens pinpointed AAVR as essential for viral uptake. Knocking out candidate genes in human cell lines revealed that cells lacking AAVR had dramatically reduced viral entry, confirming its role as a primary receptor. RNA interference (RNAi) approaches further validated these findings.

Structural techniques such as cryo-electron microscopy and X-ray crystallography provided high-resolution insights into AAVR’s interactions with AAV capsids. These studies clarified the molecular determinants of AAV attachment. Advanced imaging techniques, including Förster resonance energy transfer (FRET) and single-molecule tracking, have visualized real-time receptor-virus interactions at the cellular membrane. These findings have guided the design of engineered viral vectors with enhanced specificity.

Biochemical assays such as co-immunoprecipitation and pull-down experiments have mapped AAVR’s interactions with intracellular trafficking proteins. Live-cell imaging and super-resolution microscopy have tracked the intracellular fate of AAVR-bound particles, elucidating the stepwise progression from endocytosis to nuclear entry. Proteomic analyses have identified post-translational modifications, such as glycosylation, that influence receptor function and viral binding efficiency.

Association With Disease Pathways

AAVR’s role extends beyond viral entry and gene therapy, with emerging evidence linking it to various disease mechanisms. Alterations in AAVR expression or function have been associated with neurodevelopmental disorders and cognitive impairments. Mutations in KIAA0319L correlate with conditions such as autism spectrum disorders and intellectual disabilities, likely due to disruptions in receptor-mediated endocytosis and protein recycling. AAVR’s interactions with intracellular transport pathways suggest a broader role in neuronal homeostasis.

In cancer biology, AAVR may influence tumor progression and metastasis. Some malignancies show altered AAVR expression, with upregulation linked to increased tumor cell invasiveness. Conversely, reduced receptor levels in specific cancers have been associated with impaired cellular communication and disrupted signaling pathways. These findings have sparked interest in whether AAVR-targeting strategies could be leveraged for therapeutic interventions, either by modulating receptor function to control tumor growth or using AAV-based gene delivery to selectively target cancer cells.

AAVR’s role in lysosomal and endosomal transport also raises questions about its involvement in lysosomal storage disorders, where defective trafficking leads to toxic cellular waste accumulation. As research continues, understanding AAVR’s disease-associated functions may open new avenues for treatment strategies beyond viral vector applications.