Adeno-associated Virus Vectors Serotype 2 Induce Prolonged Proliferation of Capsid-Specific CD8+ T Cells in Mice

Li, Hua; Tuyishime, Steven; Wu, Te-Lang; Giles-Davis, Wynetta; Zhou, Dongming; Xiao, Weidong; High, Katherine A.; Ertl, Hildegund C. J.

doi:10.1038/mt.2010.267

Cited by 29 publications

(28 citation statements)

References 32 publications

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“…by guest www.bloodjournal.org From corresponding receptors for several weeks following hepatic transfer of the vector. 29 It is possible that cell lysis as tested here requires higher levels of surface-expressed MHC I-peptide complexes compared with T-cell proliferation as was tested in our previous studies. Nonetheless, there is another interesting similarity between the mouse model and clinical studies.…”

Section: Ctl-mediated Killing Is Less Efficient Against Hepatocytes Tmentioning

confidence: 92%

“…Immunization against capsid by various methods designed to induce capsid-specific CD8 1 T cells failed to eliminate transduced cells in mice, 20,24-28 despite major histocompatibility complex class I (MHC I) presentation of capsid for several weeks following AAV gene transfer. 29 A more recent study showed some effect when a strong heterologous CD8 1 T-cell epitope was incorporated into the capsid. 30 Surprisingly, nonhuman primates, who are also natural hosts for AAVs, have also not been suitable models.…”

Section: Introductionmentioning

confidence: 99%

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Engineered AAV vector minimizes in vivo targeting of transduced hepatocytes by capsid-specific CD8+ T cells

Martino

Basner-Tschakarjan

Markusic

et al. 2013

Blood

146

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Section: Ctl-mediated Killing Is Less Efficient Against Hepatocytes Tmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Engineered AAV vector minimizes in vivo targeting of transduced hepatocytes by capsid-specific CD8+ T cells

Martino

Basner-Tschakarjan

Markusic

et al. 2013

Blood

146

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show abstract

“…Multiple attempts to generate a mouse model failed. [74][75][76] More recent attempts that have made use of systems that increase the frequency of epitope-specific T cells (incorporation of SIINFEKL peptide epitopes into the AAV vector capsid and use of OT-1 mice 77 ), or that further promote the adaptive immune response through the use of adjuvants, 78 have allowed recapitulation of some features of the human response to AAV-mediated liver-directed gene transfer, but their utility in devising solutions in humans remains to be demonstrated. Because NHPs are also natural hosts for some serotypes of AAV, it seemed logical that one could model the human immune response in these animals, but multiple attempts to do so have also failed.…”

Section: Immune Responses In Aav Gene Therapy 25mentioning

confidence: 99%

Immune responses to AAV vectors: overcoming barriers to successful gene therapy

Mingozzi

High

2013

Blood

736

640

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Gene therapy products for the treatment of genetic diseases are currently in clinical trials, and one of these, an adeno-associated viral (AAV) product, has recently been licensed. AAV vectors have achieved positive results in a number of clinical and preclinical settings, including hematologic disorders such as the hemophilias, Gaucher disease, hemochromatosis, and the porphyrias. Because AAV vectors are administered directly to the patient, the likelihood of a host immune response is high, as shown by human studies. Preexisting and/or recall responses to the wild-type virus from which the vector is engineered, or to the transgene product itself, can interfere with therapeutic efficacy if not identified and managed optimally. Small-scale clinical studies have enabled investigators to dissect the immune responses to the AAV vector capsid and to the transgene product, and to develop strategies to manage these responses to achieve long-term expression of the therapeutic gene. However, a comprehensive understanding of the determinants of immunogenicity of AAV vectors, and of potential associated toxicities, is still lacking. Careful immunosurveillance conducted as part of ongoing clinical studies will provide the basis for understanding the intricacies of the immune response in AAV-mediated gene transfer, facilitating safe and effective therapies for genetic diseases.

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“…They combine several advantageous features, including a good safety profile, stable long-term gene expression in several tissues, the ability to transduce dividing and nondividing cells, and physicochemical stability (11,66). AAV vectors show generally a low innate immunity, as well as low efficiency to transduce professional antigen-presenting cells (87), although recent studies warrant a more differentiated view of the immune response to AAV-mediated gene transfer (8,22,23,26,29,32,33,37,50,65,84,88). Humoral immune responses are generated and memory CD8 ϩ T-cell responses have been observed in clinical trials (36,40,58).…”

mentioning

confidence: 99%

The Threefold Protrusions of Adeno-Associated Virus Type 8 Are Involved in Cell Surface Targeting as Well as Postattachment Processing

Raupp

Naumer

Müller

et al. 2012

J Virol

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Adeno-associated virus (AAV) has attracted considerable interest as a vector for gene therapy owing its lack of pathogenicity and the wealth of available serotypes with distinct tissue tropisms. One of the most promising isolates for vector development, based on its superior gene transfer efficiency to the liver in small animals compared to AAV type 2 (AAV2), is AAV8. Comparison of the in vivo gene transduction of rAAV2 and rAAV8 in mice showed that single amino acid exchanges in the 3-fold protrusions of AAV8 in the surface loops comprised of residues 581 to 584 and 589 to 592 to the corresponding amino acids of AAV2 and vice versa had a strong influence on transduction efficiency and tissue tropism. Surprisingly, not only did conversion of AAV8 to AAV2 cap sequences increase the transduction efficiency and change tissue tropism but so did the reciprocal conversion of AAV2 to AAV8. Insertion of new peptide motifs at position 590 in AAV8 also enabled retargeting of AAV8 capsids to specific tissues, suggesting that these sequences can interact with receptors on the cell surface. However, a neutralizing monoclonal antibody that binds to amino acids 588 QQNTA 592 of AAV8 does not prevent cell binding and virus uptake, indicating that this region is not necessary for receptor binding but rather that the antibody interferes with an essential step of postattachment processing in which the 3-fold protrusion is also involved. This study supports a multifunctional role of the 3-fold region of AAV capsids in the infection process.

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Adeno-associated Virus Vectors Serotype 2 Induce Prolonged Proliferation of Capsid-Specific CD8+ T Cells in Mice

Cited by 29 publications

References 32 publications

Engineered AAV vector minimizes in vivo targeting of transduced hepatocytes by capsid-specific CD8+ T cells

Engineered AAV vector minimizes in vivo targeting of transduced hepatocytes by capsid-specific CD8+ T cells

Immune responses to AAV vectors: overcoming barriers to successful gene therapy

The Threefold Protrusions of Adeno-Associated Virus Type 8 Are Involved in Cell Surface Targeting as Well as Postattachment Processing

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