Strategies for Evading Cellular Immunity Against Recombinant AAV Vectors in Gene Therapy

Abstract

Over the past decade, adeno-associated virus (AAV) vectors have emerged as a powerful tool for in vivo gene transfer, owing to their diverse tissue tropisms, predominantly non-integrative property, and superior safety profile compared with other viral vectors. As of December 2025, ten gene therapies based on recombinant AAV (rAAV) vectors have been approved globally, primarily by the Food and Drug Administration (FDA) and/or the European Medicines Agency (EMA). However, seroprevalence surveys indicate that most individuals carry anti-AAV neutralizing antibodies (NAbs), and nearly 50% of healthy individuals exhibit detectable frequencies of circulating AAV capsid-specific CD8⁺ T cells and/or CD4⁺ T cells. Clinical studies suggest that immune responses mediated by cytotoxic T lymphocytes (CTLs) targeting transduced cells are a key factor limiting the long-term effectiveness of rAAV-mediated gene therapy. Herein, we summarize strategies to evade anti-rAAV cellular immunity, discussing their advantages and limitations in the context of the rAAV transduction process and mechanisms of cellular immune responses. Furthermore, we highlight key challenges in research on rAAV gene therapy immunogenicity, as well as emerging technologies with potential applications in this field.

Keywords

Cellular immunity / Adeno-associated virus / Recombinant adeno-associated virus (rAAV) / Gene therapy / Immune evasion / Cytotoxic T lymphocytes (CTLs) / CD8⁺ T cells / Immunogenicity

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Funding

Natural Science Foundation of Beijing Municipality(7252208)

National High-Level Hospital Clinical Research Funding(2022-PUMCH-C-059)

Noncommunicable Chronic Diseases-National Science and Technology Major Project(No.2024ZD0533000)

The Prospective Research Program of Changzhou Xitaihu Development Foundation for Frontier Cell-Therapeutic Technology(No: 2022-P-006)

The Fundamental Research Funds for the Central Universities, Peking Union Medical College(No.3332025127)

RIGHTS & PERMISSIONS

The Author(s), under exclusive licence to the Huazhong University of Science and Technology