Gene therapy vectors based on adeno-associated virus type 1

J Virol. 1999 May;73(5):3994-4003. doi: 10.1128/JVI.73.5.3994-4003.1999.

Abstract

The complete sequence of adeno-associated virus type 1 (AAV-1) was defined. Its genome of 4,718 nucleotides demonstrates high homology with those of other AAV serotypes, including AAV-6, which appears to have arisen from homologous recombination between AAV-1 and AAV-2. Analysis of sera from nonhuman and human primates for neutralizing antibodies (NAB) against AAV-1 and AAV-2 revealed the following. (i) NAB to AAV-1 are more common than NAB to AAV-2 in nonhuman primates, while the reverse is true in humans; and (ii) sera from 36% of nonhuman primates neutralized AAV-1 but not AAV-2, while sera from 8% of humans neutralized AAV-2 but not AAV-1. An infectious clone of AAV-1 was isolated from a replicated monomer form, and vectors were created with AAV-2 inverted terminal repeats and AAV-1 Rep and Cap functions. Both AAV-1- and AAV-2-based vectors transduced murine liver and muscle in vivo; AAV-1 was more efficient for muscle, while AAV-2 transduced liver more efficiently. Strong NAB responses were detected for each vector administered to murine skeletal muscle; these responses prevented readministration of the same serotype but did not substantially cross-neutralize the other serotype. Similar results were observed in the context of liver-directed gene transfer, except for a significant, but incomplete, neutralization of AAV-1 from a previous treatment with AAV-2. Vectors based on AAV-1 may be preferred in some applications of human gene therapy.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • Base Sequence
  • Cell Line, Transformed
  • DNA, Viral
  • Dependovirus* / genetics
  • Dependovirus* / immunology
  • Disease Models, Animal
  • Genetic Therapy / methods*
  • Genetic Vectors* / genetics
  • Genetic Vectors* / immunology
  • Genome, Viral
  • Humans
  • Macaca mulatta
  • Mice
  • Mice, Inbred C57BL
  • Middle Aged
  • Molecular Sequence Data
  • Recombination, Genetic
  • Sequence Homology, Nucleic Acid

Substances

  • DNA, Viral

Associated data

  • GENBANK/AF063497