Skip to main content

Cytotoxic-T-lymphocyte-mediated elimination of target cells transduced with engineered adeno-associated virus type 2 vector in vivo.

Publication ,  Journal Article
Li, C; Hirsch, M; DiPrimio, N; Asokan, A; Goudy, K; Tisch, R; Samulski, RJ
Published in: J Virol
July 2009

A recent clinical trial in patients with hemophilia B has suggested that adeno-associated virus (AAV) capsid-specific cytotoxic T lymphocytes (CTLs) eliminated AAV-transduced hepatocytes and resulted in therapeutic failure. AAV capsids elicit a CTL response in animal models; however, these capsid-specific CTLs fail to kill AAV-transduced target cells in mice. To better model the human clinical trial data in mice, we introduced an immunodominant epitope derived from ovalbumin (OVA; SIINFEKL) into the AAV capsid and tested CTL-mediated killing of AAV2-transduced target tissues in vivo. Initially, in vitro experiments demonstrated both classical class I and cross-presentation of the OVA antigen, following endogenous expression or AAV2-OVA vector transduction, respectively. Furthermore, an OVA-specific CTL response was elicited after muscular or systemic injection of the AAV2-OVA vector. Finally, CTL reactivity was enhanced in mice with established SIINFEKL-specific immunity after AAV2-OVA/alpha1 anti-trypsin (AAT) administration. Most importantly, these OVA-specific CTLs decreased AAT expression in mice treated with AAV2-OVA/AAT vector that followed a time course mimicking uncoating kinetics of AAV2 transduction in OVA-immunized mice. These results demonstrate that AAV capsid-derived antigens elicit CD8(+) CTL reactivity, and these CTLs eliminated AAV-transduced target cells in mice. Notably, this model system can be exploited to study the kinetics of capsid presentation from different serotypes of AAV and permit the design of novel strategies to block CTL-mediated killing of AAV-transduced cells.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

J Virol

DOI

EISSN

1098-5514

Publication Date

July 2009

Volume

83

Issue

13

Start / End Page

6817 / 6824

Location

United States

Related Subject Headings

  • Virology
  • Transfection
  • T-Lymphocytes, Cytotoxic
  • Peptide Fragments
  • Ovalbumin
  • Mice, Transgenic
  • Mice, Inbred C57BL
  • Mice, Inbred BALB C
  • Mice
  • Immunodominant Epitopes
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Li, C., Hirsch, M., DiPrimio, N., Asokan, A., Goudy, K., Tisch, R., & Samulski, R. J. (2009). Cytotoxic-T-lymphocyte-mediated elimination of target cells transduced with engineered adeno-associated virus type 2 vector in vivo. J Virol, 83(13), 6817–6824. https://doi.org/10.1128/JVI.00278-09
Li, Chengwen, Matt Hirsch, Nina DiPrimio, Aravind Asokan, Kevin Goudy, Roland Tisch, and R Jude Samulski. “Cytotoxic-T-lymphocyte-mediated elimination of target cells transduced with engineered adeno-associated virus type 2 vector in vivo.J Virol 83, no. 13 (July 2009): 6817–24. https://doi.org/10.1128/JVI.00278-09.
Li C, Hirsch M, DiPrimio N, Asokan A, Goudy K, Tisch R, et al. Cytotoxic-T-lymphocyte-mediated elimination of target cells transduced with engineered adeno-associated virus type 2 vector in vivo. J Virol. 2009 Jul;83(13):6817–24.
Li, Chengwen, et al. “Cytotoxic-T-lymphocyte-mediated elimination of target cells transduced with engineered adeno-associated virus type 2 vector in vivo.J Virol, vol. 83, no. 13, July 2009, pp. 6817–24. Pubmed, doi:10.1128/JVI.00278-09.
Li C, Hirsch M, DiPrimio N, Asokan A, Goudy K, Tisch R, Samulski RJ. Cytotoxic-T-lymphocyte-mediated elimination of target cells transduced with engineered adeno-associated virus type 2 vector in vivo. J Virol. 2009 Jul;83(13):6817–6824.

Published In

J Virol

DOI

EISSN

1098-5514

Publication Date

July 2009

Volume

83

Issue

13

Start / End Page

6817 / 6824

Location

United States

Related Subject Headings

  • Virology
  • Transfection
  • T-Lymphocytes, Cytotoxic
  • Peptide Fragments
  • Ovalbumin
  • Mice, Transgenic
  • Mice, Inbred C57BL
  • Mice, Inbred BALB C
  • Mice
  • Immunodominant Epitopes