Adeno-associated viruses (AAVs) are small, non-disease-causing viruses frequently used as delivery vehicles in gene therapy. Scientists can engineer these viruses to carry therapeutic genes into human cells, making them a tool for treating genetic disorders. For a virus to enter a cell, it must first connect with a cellular receptor on the cell’s surface. The AAV receptor is the specific molecule that an AAV particle latches onto to begin its entry into a cell.
Defining AAV Receptors
AAV receptors are molecules located on the surface of host cells that the virus uses to gain entry. These are typically proteins or sugar chains known as glycans. The presence of the correct receptor is a determining factor for whether an AAV can successfully infect a particular cell. A significant discovery in this field was the identification of a protein called AAVR, which acts as a receptor for many different types of AAVs.
AAVR is a protein that passes through the cell membrane, with a portion of it exposed on the outside of the cell. This external part, or ectodomain, contains five distinct structures that AAV particles directly bind to. This direct binding to a protein receptor like AAVR is a necessary step for viral entry.
The interaction is highly specific; the virus’s outer shell, or capsid, has a structure that recognizes and binds to these cellular molecules. This specificity is a core principle in how AAVs are used in medicine. A cell that lacks the appropriate receptor for a certain AAV will be resistant to infection by it.
How AAVs Use Receptors for Cell Entry
The process of an AAV entering a cell is a multi-step interaction with surface receptors. It begins with an initial attachment, where the AAV particle first makes contact with the cell. This binding is often to abundant glycan molecules, which act as an anchor, holding the virus on the cell surface.
Following this initial tethering, the AAV particle engages with a more specific protein co-receptor like AAVR. This secondary binding event is what triggers the cell to internalize the virus by signaling the cell to envelop the viral particle.
The cell engulfs the AAV through a process called endocytosis, where the cell membrane folds inward to form a vesicle, or small bubble, containing the virus. This vesicle, known as an endosome, is then transported from the cell periphery toward the cell’s interior.
Once inside, the AAV must navigate the cell’s internal environment to deliver its genetic material to the nucleus, where it can be used by the cell’s machinery. The efficiency of this entire process, from initial binding to nuclear entry, is influenced by the number and type of receptors on the cell surface.
AAV Serotypes and Receptor Specificity
AAVs exist as numerous variants known as serotypes, which are naturally occurring versions of the virus with small differences in their capsid. The capsid is the protein shell enclosing the viral DNA. These structural variations determine which receptors an AAV serotype can bind to.
The specificity of this virus-receptor interaction drives tissue tropism—the natural inclination of a serotype to infect certain cells more readily than others. A serotype whose capsid proteins bind to receptors on liver cells will naturally target the liver. For instance, AAV8 is often favored for liver-directed gene therapies.
This relationship between capsid structure and receptor preference explains the diversity seen in AAV behavior. Some serotypes might bind to a receptor that is widespread throughout the body, giving them broad tropism. Others may interact with a receptor that is unique to a specific organ, like the brain or muscle tissue.
Scientists exploit these differences by selecting specific serotypes for different therapeutic applications. If a gene therapy is intended to correct a genetic defect in the retina, a researcher would choose an AAV serotype known to effectively bind to receptors on retinal cells. This selection process is a key part of designing AAV-based treatments.
The Role of AAV Receptors in Gene Therapy
Understanding AAV receptors has significant practical importance for the field of gene therapy. This knowledge directly informs the design and application of AAV vectors, enabling scientists to develop safer and more effective treatments.
This knowledge also allows for engineering AAV capsids to improve their performance by modifying the virus’s outer protein shell to change its receptor binding properties. This can be done to enhance the targeting of desired cells, increasing the therapy’s effectiveness. Conversely, capsids can be engineered to avoid binding to cells where the vector might cause unwanted side effects.
A detailed understanding of receptor interactions helps address challenges in gene therapy like pre-existing immunity. A patient may have antibodies that block the AAV from binding to its receptor, rendering the therapy ineffective. By creating AAV variants that bind to different receptors, it may be possible to bypass this immune response.
Knowledge of receptor density and distribution on target cells also guides dosing strategies. If target cells have a low number of receptors, a higher dose of the AAV vector may be needed to achieve a therapeutic effect.