Type I IFN Sensing by cDCs and CD4+ T Cell Help Are Both Requisite for Cross-Priming of AAV Capsid-Specific CD8+ T Cells

Shirley, Jamie L.; Keeler, Geoffrey D.; Sherman, Alexandra; Zolotukhin, Irene; Markusic, David M.; Hoffman, Brad E.; Morel, Laurence; Wallet, Mark A.; Terhorst, Cox; Herzog, Roland W.

doi:10.1016/j.ymthe.2019.11.011

Cited by 55 publications

(56 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“… 69 This process requires T1 IFN, which binds to its receptor on cDCs, suggesting a direct effect of cytokine production by pDCs on cDC activation. 70 However, NK cells, which may indirectly mediate the effect of pDCs on cDCs, are not required. In addition to T1 IFN, CD40-CD40L co-stimulation, which is carried out by CD4 + Th cells, is required for cross-priming of CD8 + T cells against AAV capsid.…”

Section: Main Textmentioning

confidence: 99%

Immune Responses to Viral Gene Therapy Vectors

et al. 2020

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Main Textmentioning

confidence: 99%

Immune Responses to Viral Gene Therapy Vectors

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…In the context of rAAV-mediated gene transfer, preclinical studies supported the important role of type I IFNs in the induction of CD8 + T cell responses. In particular, blocking the activation of innate immune responses prevented both cytotoxic (66,67) and humoral (52) anti-capsid responses in vivo.…”

Section: Post-treatment Immune Responses Against Aav Vectors Innate Imentioning

confidence: 99%

“…Activated CD8 + T cells may clear rAAVtransduced cells thus inducing inflammation in the target organ, affecting the gene transfer outcome (45,51,77,78). The concurrent presentation of capsid-derived MHC class II epitopes by professional APCs activates CD4 + T helper cells, which facilitate humoral and cell-mediated immune responses (67). Indeed, experience from clinical trials indicate that rAAV vectors administration leads to the development of anti-AAV IgG and NAbs (42), likely preventing vector readministration.…”

Section: Adaptive Immune System Activation Following Raav Administrationmentioning

confidence: 99%

Human Immune Responses to Adeno-Associated Virus (AAV) Vectors

2020

View full text Add to dashboard Cite

Recombinant adeno-associated virus (rAAV) vectors are one of the most promising in vivo gene delivery tools. Several features make rAAV vectors an ideal platform for gene transfer. However, the high homology with the parental wild-type virus, which often infects humans, poses limitations in terms of immune responses associated with this vector platform. Both humoral and cell-mediated immunity to wild-type AAV have been documented in healthy donors, and, at least in the case of anti-AAV antibodies, have been shown to have a potentially high impact on the outcome of gene transfer. While several factors can contribute to the overall immunogenicity of rAAV vectors, vector design and the total vector dose appear to be responsible of immune-mediated toxicities. While preclinical models have been less than ideal in predicting the outcome of gene transfer in humans, the current preclinical body of evidence clearly demonstrates that rAAV vectors can trigger both innate and adaptive immune responses. Data gathered from clinical trials offers key learnings on the immunogenicity of AAV vectors, highlighting challenges as well as the potential strategies that could help unlock the full therapeutic potential of in vivo gene transfer.

show abstract

“… 25 , 48 , 49 , 50 , 51 Elimination of phosphorylation sites therefore enhances transfer to the nucleus and reduces presentation of peptides derived from proteasomal degradation, therefore reducing the likelihood of being targeted by capsid-specific CD8 + T cells. 9 , 50 , 52 , 53 When attempting to optimize the AAV3B capsid, elimination of a serine and a threonine site (S663V+T492V mutations) was found to be more efficacious 33 , 43 , 44 for transduction of human and non-human primate hepatocytes. In this study, we diversified the T 492 position to include either of the following positions: T/I/A/V, while leaving S 663 as in the WT AAV3B.…”

Section: Discussionmentioning

confidence: 99%

Engineering and In Vitro Selection of a Novel AAV3B Variant with High Hepatocyte Tropism and Reduced Seroreactivity

Biswas

Marsic

et al. 2020

Molecular Therapy - Methods & Clinical Development

Self Cite

View full text Add to dashboard Cite

Limitations to successful gene therapy with adeno-associated virus (AAV) can comprise pre-existing neutralizing antibodies to the vector capsid that can block cellular entry, or inefficient transduction of target cells that can lead to sub-optimal expression of the therapeutic transgene. Recombinant serotype 3 AAV (AAV3) is an emerging candidate for liver-directed gene therapy. In this study, we integrated rational design by using a combinatorial library derived from AAV3B capsids with directed evolution by in vitro selection for liver-targeted AAV variants. The AAV3B-DE5 variant described herein was undetectable in the original viral library but gained a selective advantage upon in vitro passaging in human hepatocarcinoma spheroid cultures. AAV3B-DE5 contains 24 capsid amino acid substitutions compared with AAV3B, distributed among all five variable regions, with strong selective pressure on VR-IV, VR-V, and VR-VII. In vivo , AAV3B-DE5 demonstrated improved human hepatocyte tropism in a liver chimeric mouse model. Importantly, this variant exhibited reduced seroreactivity to human intravenous immunoglobulin (i.v. Ig), as well as individual serum samples from 100 healthy human donors. Therefore, molecular evolution using a combinatorial library platform generated a viral capsid with high hepatocyte tropism and enhanced evasion of pre-existing AAV neutralizing antibodies.

show abstract

Type I IFN Sensing by cDCs and CD4+ T Cell Help Are Both Requisite for Cross-Priming of AAV Capsid-Specific CD8+ T Cells

Cited by 55 publications

References 67 publications

Immune Responses to Viral Gene Therapy Vectors

Immune Responses to Viral Gene Therapy Vectors

Human Immune Responses to Adeno-Associated Virus (AAV) Vectors

Engineering and In Vitro Selection of a Novel AAV3B Variant with High Hepatocyte Tropism and Reduced Seroreactivity

Contact Info

Product

Resources

About