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Review
. 2020 Mar 4;28(3):709-722.
doi: 10.1016/j.ymthe.2020.01.001. Epub 2020 Jan 10.

Immune Responses to Viral Gene Therapy Vectors

Jamie L Shirley  1 , Ype P de Jong  2 , Cox Terhorst  3 , Roland W Herzog  4
Affiliations
Review

Immune Responses to Viral Gene Therapy Vectors

Jamie L Shirley et al. Mol Ther. .

Abstract

Several viral vector-based gene therapy drugs have now received marketing approval. A much larger number of additional viral vectors are in various stages of clinical trials for the treatment of genetic and acquired diseases, with many more in pre-clinical testing. Efficiency of gene transfer and ability to provide long-term therapy make these vector systems very attractive. In fact, viral vector gene therapy has been able to treat or even cure diseases for which there had been no or only suboptimal treatments. However, innate and adaptive immune responses to these vectors and their transgene products constitute substantial hurdles to clinical development and wider use in patients. This review provides an overview of the type of immune responses that have been documented in animal models and in humans who received gene transfer with one of three widely tested vector systems, namely adenoviral, lentiviral, or adeno-associated viral vectors. Particular emphasis is given to mechanisms leading to immune responses, efforts to reduce vector immunogenicity, and potential solutions to the problems. At the same time, we point out gaps in our knowledge that should to be filled and problems that need to be addressed going forward.

Keywords: adaptive immunity; adeno-associated virus; adenovirus; innate immunity; lentivirus.

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Figures

None
Graphical abstract
Figure 1
Figure 1
Innate Immune Sensing and Signaling Pathways that Contribute to Immune Responses to Different Viral Vectors Note that the figure illustrates some of the most common pathways but is not meant to be exhaustive. Abbreviations are as follows: dsDNA, double-stranded DNA; NLPR3, NACHT, LRR, and PYD domains-containing protein 3; ASC, adaptor protein apoptosis-associated speck-like protein containing CARD; Pro-casp 1, pro-caspase 1; IFNAR-1, interferon α/β receptor 1; Jak1, Janus kinase 1; Tyk2, tyrosine kinase 2; Stat, signal transducer and activator of transcription; P, phosphoryl group; MDA5, melanoma differentiation-associated protein 5; dsRNA, double-stranded RNA; RIG-I, retinoic acid-inducible gene-I; MAVS, mitochondrial antiviral signaling protein; STING, stimulator of interferon genes; IRF, interferon response factor; cGAS, cyclic guanosine monophosphate-AMP synthase; TLR, Toll-like receptor; ISG, interferon-stimulated genes; IFN, interferon; MyD88, myeloid differentiation primary response protein 88; NF-κB, nuclear factor κ-light-chain-enhancer of activated B cells; and ssRNA, single-stranded RNA.
Figure 2
Figure 2
Examples of Molecular Structures and Antigens in Viral Vectors that Are Recognized by Innate Immune Sensors or Targeted by Antigen-Specific Adaptive (B and T Cell) Immune Responses (A) Adenoviral vectors. (B) AAV vectors. (C) Lentiviral vectors. Abbreviations are as follows: dsDNA, double-stranded DNA; TLR, Toll-like receptor; cGAS, cyclic guanosine monophosphate-AMP synthase; IFN, interferon; APC, antigen-presenting cell; CTL, cytotoxic T lymphocyte; dsRNA, double-stranded RNA; MDA5, melanoma differentiation-associated protein 5; pDC, plasmacytoid dendritic cell; and ssRNA, single-stranded RNA.
Figure 3
Figure 3
Model for the Immune Response Mechanism Against AAV Vectors Cooperation between pDCs (that sense the AAV genome via TLR9 and produce T1 IFN), cDCs (that present antigen), and CD4+ T helper cells (that provide co-stimulation via the CD40-CD40L pathway) leads to activation of CD8+ T cells. Antibody formation also depends on CD4+ T helper cells and is augmented by activation of moDCs, resulting in IL-1β and IL-6 pro-inflammatory cytokine production, and is modulated by T1 IFN. Abbreviations are as follows: IFNAR-1, interferon α/β receptor 1; cDC, conventional dendritic cell; pDC, plasmacytoid dendritic cell; IFN, interferon; TLR, Toll-like receptor; MyD88, myeloid differentiation primary response protein 88; MHC, major histocompatibility complex; moDC, monocyte-derived dendritic cell; and CD, cluster of differentiation.
Figure 4
Figure 4
Strategy to Eliminate Transgene Expression from Lentiviral Vectors in Professional Antigen-Presenting Cells This approach can also be applied to other viral vectors such as AAV and adenovirus. (A) Incorporation of multiple repeats of a target for a miRNA that is highly expressed in hematopoietic cells into the transcript of the transgene results in efficient degradation of the transgene message, thereby preventing transgene expression in an APC. (B) Transduction of a target cell for therapeutic gene expression such as a hepatocyte that does not express the miRNA results in transgene expression. Abbreviations are as follows: APC, antigen-presenting cell; miRNA, micoRNA; mRNA, messenger RNA; and RISC, RNA-induced silencing complex.
Figure 5
Figure 5
Potential Targets for Directed Pharmacological Interventions to Prevent Immunotoxicities and Lower the Risk of Innate and Adaptive Immune Responses in Viral Vector Gene Transfer Immunoglobulins in red indicate blockage of a pathway with a monoclonal antibody. Abbreviations are as follows: cGAS, cyclic guanosine monophosphate-AMP synthase; CTL, cytotoxic T lymphocyte; DC, dendritic cell; IL, interleukin; INF, interferon; MDA5, melanoma differentiation-associated protein 5; MF, macrophage; mTOR, mammalian target of rapamycin; RIG-I, retinoic acid-inducible gene I; Teff, effector T cell; TLR, Toll-like receptor; and Treg, regulatory T cell. Receptor for a specific cytokine is indicated with “R” after the cytokine name.
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