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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.
J Virol 2004; 78(12):6344-59JV

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.

Authors+Show Affiliations

University of Florida College of Medicine, P.O. Box 100244, Gainesville, FL 32610, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15163728

Citation

Peden, Carmen S., et al. "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." Journal of Virology, vol. 78, no. 12, 2004, pp. 6344-59.
Peden CS, Burger C, Muzyczka N, et al. 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. J Virol. 2004;78(12):6344-59.
Peden, C. S., Burger, C., Muzyczka, N., & Mandel, R. J. (2004). 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. Journal of Virology, 78(12), pp. 6344-59.
Peden CS, et al. 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. J Virol. 2004;78(12):6344-59. PubMed PMID: 15163728.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Peden,Carmen S, AU - Burger,Corinna, AU - Muzyczka,Nicholas, AU - Mandel,Ronald J, PY - 2004/5/28/pubmed PY - 2004/6/30/medline PY - 2004/5/28/entrez SP - 6344 EP - 59 JF - Journal of virology JO - J. Virol. VL - 78 IS - 12 N2 - 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. SN - 0022-538X UR - https://www.unboundmedicine.com/medline/citation/15163728/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_ L2 - http://jvi.asm.org/cgi/pmidlookup?view=long&pmid=15163728 DB - PRIME DP - Unbound Medicine ER -