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Related Experiment Videos

Replication-defective vector based on a chimpanzee adenovirus.

S F Farina1, G P Gao, Z Q Xiang

  • 1Institute for Human Gene Therapy and Department of Molecular and Cellular Engineering, University of Pennsylvania, Philadelphia, USA.

Journal of Virology
|November 2, 2001
PubMed
Summary
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A novel chimpanzee adenovirus, C68, shows high similarity to human adenoviruses but unique hexon regions. This distinct chimpanzee adenovirus vector avoids cross-neutralization by human adenovirus antibodies.

Area of Science:

  • Virology
  • Molecular Biology
  • Gene Therapy Vectors

Background:

  • Adenoviruses are widely used as gene therapy vectors due to their safety and efficacy.
  • Developing novel adenoviral vectors with improved properties, such as reduced pre-existing immunity, is crucial for advancing gene therapy.
  • Chimpanzee adenoviruses represent a potential source of new vectors distinct from human adenoviruses.

Purpose of the Study:

  • To fully sequence and characterize a chimpanzee adenovirus (C68) for its potential as a gene therapy vector.
  • To evaluate the cross-neutralization profile of C68 and its vector derivatives against human adenoviruses.
  • To assess the utility of C68 as a replication-defective vector for human and murine cell transduction.

Main Methods:

  • Full genome sequencing of the chimpanzee adenovirus C68.

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  • Comparative genomic analysis with human adenovirus subgroups.
  • Construction of a replication-defective C68 vector (C68 E1a/E1b deleted) and assessment of its transcomplementation and transduction capabilities.
  • Serological assays to evaluate neutralizing antibody responses in chimpanzees, humans, rhesus monkeys, and mice.
  • Main Results:

    • The C68 genome (36,521 bp) is structurally similar to human adenoviruses, particularly subgroup E, with 90% identity in sequenced open reading frames.
    • Significant differences were observed in the hexon hypervariable regions between C68 and human adenoviruses, including adenovirus type 4.
    • Neutralizing antibodies against C68 were prevalent in chimpanzees but absent in humans and rhesus monkeys; C68 was not neutralized by sera from mice immunized with common human adenovirus serotypes.
    • A replication-defective C68 vector was efficiently transcomplemented by human adenovirus type 5 E1 region and transduced human and murine cell lines, including those expressing the coxsackievirus and adenovirus receptor (CAR).

    Conclusions:

    • Chimpanzee adenovirus C68 is a viable candidate for developing novel adenoviral vectors.
    • The unique hexon hypervariable regions of C68 contribute to its distinct serological profile, avoiding cross-neutralization by antibodies against common human adenoviruses.
    • C68-based vectors offer a promising alternative for gene therapy, particularly in populations with pre-existing immunity to human adenoviruses.