Circulating Anti-Wild-Type Adeno-Associated Virus Type 2 (AAV2) Antibodies Inhibit Recombinant AAV2 (rAAV2)-Mediated, but Not rAAV5-Mediated, Gene Transfer in the Brain
Open Access
- 15 June 2004
- journal article
- Published by American Society for Microbiology in Journal of Virology
- Vol. 78 (12), 6344-6359
- https://doi.org/10.1128/jvi.78.12.6344-6359.2004
Abstract
Epidemiological studies report that 80% of the population maintains antibodies (Ab) to wild-type (wt) adeno-associated virus type 2 (AAV2), with 30% expressing neutralizing Ab (NAb). The blood-brain barrier (BBB) provides limited immune privilege to brain parenchyma, and the immune response to recombinant AAV (rAAV) administration in the brain of a naive animal is minimal. However, central nervous system transduction in preimmunized animals remains unstudied. Vector administration may disrupt the BBB sufficiently to promote an immune response in a previously immunized animal. We tested the hypothesis that intracerebral rAAV administration and readministration would not be affected by the presence of circulating Ab to wt AAV2. Rats peripherally immunized with live wt AAV2 and naive controls were tested with single intrastriatal injections of rAAV2 encoding human glial cell line-derived neurotrophic factor (GDNF) or green fluorescent protein (GFP). Striatal readministration of rAAV2-GDNF was also tested in preimmunized and naive rats. Finally, serotype specificity of the immunization against wt AAV2 was examined by single injections of rAAV5-GFP. Preimmunization resulted in high levels of circulating NAb and prevented transduction by rAAV2 as assessed by striatal GDNF levels. rAAV2-GFP striatal transduction was also prevented by immunization, while rAAV5-GFP-mediated transduction, as assessed by stereological cell counting, was unaffected. Additionally, inflammatory markers were present in those animals that received repeated administrations of rAAV2, including markers of a cell-mediated immune response and cytotoxic damage. A live virus immunization protocol generated the circulating anti-wt-AAV Ab seen in this experiment, while human titers are commonly acquired via natural infection. Regardless, the data show that the presence of high levels of NAb against wt AAV can reduce rAAV-mediated transduction in the brain and should be accounted for in future experiments utilizing this vector.Keywords
This publication has 44 references indexed in Scilit:
- Subthalamic GAD Gene Therapy in a Parkinson's Disease Rat ModelScience, 2002
- Immunological Aspects of Recombinant Adeno-Associated Virus Delivery to the Mammalian BrainJournal of Virology, 2002
- Preexisting Antiadenoviral Immunity Is Not a Barrier to Efficient and Stable Transduction of the Brain, Mediated by Novel High-Capacity Adenovirus VectorsHuman Gene Therapy, 2001
- CMV-β-Actin Promoter Directs Higher Expression from an Adeno-Associated Viral Vector in the Liver than the Cytomegalovirus or Elongation Factor 1α Promoter and Results in Therapeutic Levels of Human Factor X in MiceHuman Gene Therapy, 2001
- Acute Direct Adenoviral Vector Cytotoxicity and Chronic, but Not Acute, Inflammatory Responses Correlate with Decreased Vector-Mediated Transgene Expression in the BrainMolecular Therapy, 2001
- Induction of Immunity to Antigens Expressed by Recombinant Adeno-Associated Virus Depends on the Route of AdministrationClinical Immunology, 1999
- Recombinant adeno-associated virus purification using novel methods improves infectious titer and yieldGene Therapy, 1999
- Adeno-Associated Virus-Mediated Gene Transfer to the Brain: Duration and Modulation of ExpressionHuman Gene Therapy, 1999
- Pre-existing herpes simplex virus 1 (HSV-1) immunity decreases, but does not abolish, gene transfer to experimental brain tumors by a HSV-1 vectorGene Therapy, 1998
- Transient Immunosuppression Allows Transgene Expression Following Readministration of Adeno-Associated Viral VectorsHuman Gene Therapy, 1998