Optimization of AAV vectors to target persistent viral reservoirs
Open accessAbstract
Gene delivery of antiviral therapeutics to anatomical sites where viruses accumulate and persist is a promising approach for the next generation of antiviral therapies. Recombinant adeno-associated viruses (AAV) are one of the leading vectors for gene therapy applications that deliver gene-editing enzymes, antibodies, and RNA interference molecules to eliminate viral reservoirs that fuel persistent infections. As long-lived viral DNA within specific cellular reservoirs is responsible for persistent hepatitis B virus, Herpes simplex virus, and human immunodeficiency virus infections, the discovery of AAV vectors with strong tropism for hepatocytes, sensory neurons and T cells, respectively, is of particular interest. Identification of natural isolates from various tissues in humans and non-human primates has generated an extensive catalog of AAV vectors with diverse tropisms and transduction efficiencies, which has been further expanded through molecular genetic approaches. The AAV capsid protein, which forms the virions' outer shell, is the primary determinant of tissue tropism, transduction efficiency, and immunogenicity. Thus, over the past few decades, extensive efforts to optimize AAV vectors for gene therapy applications have focused on capsid engineering with approaches such as directed evolution and rational design. These approaches are being used to identify variants with improved transduction efficiencies, alternate tropisms, reduced sequestration in non-target organs, and reduced immunogenicity, and have produced AAV capsids that are currently under evaluation in pre-clinical and clinical trials. This review will summarize the most recent strategies to identify AAV vectors with enhanced tropism and transduction in cell types that harbor viral reservoirs.
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Differences in AAV tropism are determined by the AAV capsid, the primary attachment receptor, and the co-receptor specificity of each serotype.
“Differences in the tropism are determined by the AAV capsid, the primary attachment receptor, and the co-receptor specificity of each serotype (Colón-Thillet et al., 2021).”
From AAV2 and AAV9 tropism and transgene expression in the mouse eye and major tissues after intravitreal and subretinal delivery (2023) · cites this paper as Colón-Thillet et al., 2021
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- Authors
- Colón-Thillet, R., Jerome, K. R., & Stone, D.
- Affiliations
- Fred Hutch Cancer Center (US)
- University of Washington (US)
- Corresponding author
- Stone, Daniel
- Venue
- Virology Journal
- Published
- 2021-04-23
- Volume
- 18
- Issue
- 1
- Pages
- 85-85
- ISSN
- 1743-422X (ISSN-L)
- PMC
- PMC8067653
- OpenAlex
- W3154732413
- Cited by
- 50
- References
- 183
- Citations by year
- 2026: 3 · 2025: 9 · 2024: 12 · 2023: 13 · 2022: 5 · 2021: 7
- FWCI
- 1.40
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Virology Journal (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- amfAR, The Foundation for AIDS Research (109575-62-RGRL)
- National Institute of Allergy and Infectious Diseases (UM1 AI126623, 5R21AI107252-02, R21AI117519, R01AI132599)
- National Institutes of Health (P30 AI 027757)
- National Cancer Institute (P30 CA015704)
- Washington Research Foundation (Postdoctoral Fellowship)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- adeno-associated virus vectors, capsid engineering, viral tropism, antiviral gene therapy, hepatitis B virus, herpes simplex virus, HIV, hepatocytes, sensory neurons, T cells, transduction efficiency, immunogenicity, directed evolution, rational design
- MeSH terms
- Persistent Infection, Dependovirus, Animals, Antiviral Agents, Capsid, Genetic Vectors, Transduction, Genetic, Capsid Proteins
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