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Adaptive immune responses elicited by baculovirus and impacts on subsequent transgene expression in vivo.

ABSTRACT: Baculovirus (BV) is a promising gene therapy vector and typically requires readministration because BV mediates transient expression. However, how the prime-boost regimen triggers BV-specific adaptive responses and their impacts on BV readministration, transgene expression, and therapeutic/vaccine efficacy remain unknown. Here we unraveled that BV injection into BALB/c mice induced the production of BV-specific antibodies, including IgG1 and IgG2a, which could neutralize BV by antagonizing the envelope protein gp64 and impede BV-mediated transgene expression. Moreover, humans did not possess preexisting anti-BV antibodies. BV injection also elicited BV-specific Th1 and Th2 responses as well as CD4(+) and CD8(+) T cell responses. gp64 was a primary immunogen to activate the antibody and CD8(+) T cell response, with its peptide at positions 457 to 465 (peptide 457-465) being the major histocompatibility complex (MHC) class I epitope to stimulate CD8(+) T cell and cytotoxic responses. Nonetheless, a hybrid Sleeping Beauty-based BV enabled long-term expression for >1 year by a single injection, indicating that the T cell responses did not completely eradicate BV-transduced cells and implicating the potential of this hybrid BV vector for gene therapy. These data unveil that BV injection triggers adaptive immunity and benefit rational design of BV administration schemes for gene therapy and vaccination.

SUBMITTER: Luo WY

PROVIDER: S-EPMC3624290 | biostudies-other | 2013 May

REPOSITORIES: biostudies-other

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Adaptive immune responses elicited by baculovirus and impacts on subsequent transgene expression in vivo.

Luo Wen-Yi WY Lin Shih-Yeh SY Lo Kai-Wei KW Lu Chia-Hsin CH Hung Chang-Lin CL Chen Chi-Yuan CY Chang Chien-Chung CC Hu Yu-Chen YC

Journal of virology 20130213 9

Baculovirus (BV) is a promising gene therapy vector and typically requires readministration because BV mediates transient expression. However, how the prime-boost regimen triggers BV-specific adaptive responses and their impacts on BV readministration, transgene expression, and therapeutic/vaccine efficacy remain unknown. Here we unraveled that BV injection into BALB/c mice induced the production of BV-specific antibodies, including IgG1 and IgG2a, which could neutralize BV by antagonizing the e ...[more]

PMID: 23408634

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Project description:Pompe disease can be treated effectively, if immune tolerance to enzyme replacement therapy (ERT) with acid ?-glucosidase (GAA) is present. An adeno-associated viral (AAV) vector carrying a liver-specific regulatory cassette to drive GAA expression (AAV-LSPhGAA) established immune tolerance in GAA knockout (KO) mice, whereas ubiquitous expression with AAV-CBhGAA provoked immune responses. Therefore, we investigated the hypothesis that immune tolerance induced by hepatic-restricted expression was dominant. AAV-LSPhGAA and AAV-CBhGAA were administered singly or in combination to groups of adult GAA-KO mice, and AAV-LSPhGAA induced immune tolerance even in combination with AAV-CBhGAA. The dual vector approach to GAA expression improved biochemical correction of GAA deficiency and glycogen accumulations at 18 weeks, and improved motor function testing including wire-hang and grip-strength testing. The greatest efficacy was demonstrated by dual vector administration, when both vectors were pseudotyped as AAV8. T cells from mice injected with AAV-LSPhGAA failed to proliferate at all after an immune challenge with GAA and adjuvant, whereas mock-treated GAA-KO mice mounted vigorous T cell proliferation. Unlike AAV-LSPhGAA, AAV-CBhGAA induced selective cytokine and chemokine expression in liver and spleen after the immune challenge. AAV-CBhGAA transduced dendritic cells and expressed high-level GAA, whereas AAV-LSPhGAA failed to express GAA in dendritic cells. The level of transduction in liver was much higher after dual AAV8 vector administration at 18 weeks, in comparison with either vector alone. Dual vector administration failed to provoke antibody formation in response to GAA expression with AAV-CBhGAA; however, hepatic-restricted expression from dual vector expression did not prevent antibody formation after a strong immune challenge with GAA and adjuvant. The relevance of immune tolerance to gene therapy in Pompe disease indicates that hepatic expression might best be combined with nonhepatic expression, achieving the benefits of ubiquitous expression in addition to evading deleterious immune responses.

Dataset Information

Adaptive immune responses elicited by baculovirus and impacts on subsequent transgene expression in vivo.

Publications

Adaptive immune responses elicited by baculovirus and impacts on subsequent transgene expression in vivo.

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