Regulatory and Exhausted T Cell Responses to AAV Capsid.
Recombinant adeno-associated viruses (AAVs) are quickly becoming the preferred viral vector for viral gene delivery for the treatment of a wide variety of genetic disorders. However, since their use in a clinical trial targeting hemophilia B patients 10 years ago, immune responses to the AAV capsid appear to have hampered some of the early clinical gene transfer efficacy. Indeed, AAV-based gene transfer has been shown to reactivate capsid-specific memory T cells, which have correlated with a decline in AAV-transduced tissue in some patients. Importantly, clinical trials have also shown that this reactivation can be quelled by administering time-course taper of glucocorticoid steroids before or after dosing. More recently, two clinical studies have shown that AAV gene transfer is not only able to induce a deleterious immune response, but also can result in the initiation of a tolerance to the AAV capsid mediated by regulatory T cells and exhausted T cells. This article reviews clinical trials describing immune responses to AAV, as well as the mechanisms responsible for immune tolerance in chronic infections and how it could apply to AAV-based gene transfer. A better understanding of both cytotoxic and tolerogenic immune responses to recombinant AAV will lead to safer gene transfer protocols in patients.
1 Gene Therapy Center, University of Massachusetts Medical School , Worcester, Massachusetts.
Gwladys
G
Gernoux
2 Gene Therapy Program, Department of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania.
James M
JM
Wilson
1 Gene Therapy Center, University of Massachusetts Medical School , Worcester, Massachusetts.
Christian
C
Mueller
D036022:Capsid Proteins / Q000276:immunology / Q000627:therapeutic use*; D000229:Dependovirus / Q000235:genetics* / Q000276:immunology; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000009:adverse effects*; D005822:Genetic Vectors / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use; D006801:Humans; D007111:Immunity, Cellular; D013601:T-Lymphocytes / Q000276:immunology
D036022:Capsid Proteins
AAV; CTL; T cell exhaustion; Treg; immune response; regulatory T cell