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Adeno-associated virus serotype 2 induces cell-mediated immune responses directed against multiple epitopes of the capsid protein VP1.

Madsen, Declan and Cantwell, Emma R. and O'Brien, Timothy and Johnson, Patricia A. and Mahon, Bernard P. (2009) Adeno-associated virus serotype 2 induces cell-mediated immune responses directed against multiple epitopes of the capsid protein VP1. Journal of General Virology, 90 (11). pp. 2622-2633. ISSN 1465-2099

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Official URL: http://jgv.sgmjournals.org/cgi/reprint/90/11/2622

Abstract

Adeno-associated virus serotype 2 (AAV-2) has been developed as a gene therapy vector. Antibody and cell-mediated immune responses to AAV-2 or AAV-2-transfected cells may confound the therapeutic use of such vectors in clinical practice. In one of the most detailed examinations of AAV-2 immunity in humans to date, cell-mediated and humoral immune responses to AAV-2 were characterized from a panel of healthy blood donors. The extent of AAV-2-specific antibody in humans was determined by examination of circulating AAV-2-specific total IgG levels in plasma from 45 normal donors. Forty-one donors were seropositive and responses were dominated by IgG1 and IgG2 subclasses. Conversely, AAV-2-specific IgG3 levels were consistently low in all donors. Cell-mediated immune recall responses were detectable in nearly half the population studied. In vitro restimulation with AAV-2 of peripheral blood mononuclear cell cultures from 16 donors elicited gamma interferon (IFN-c) (ten donors), interleukin-10 (IL-10) (eight donors) and interleukin-13 (IL-13) (four donors) responses. Using a series of overlapping peptides derived from the sequence of the VP1 viral capsid protein, a total of 59 candidate T-cell epitopes were identified. Human leukocyte antigen characterization of donors revealed that the population studied included diverse haplotypes, but that at least 17 epitopes were recognized by multiple donors and could be regarded as immunodominant. These data indicate that robust immunological memory to AAV-2 is established. The diversity of sequences recognized suggests that attempts to modify the AAV-2 capsid, as a strategy to avoid confounding immunity, will not be feasible.

Item Type: Article
Keywords: Adeno-associated virus serotype 2 (AAV-2); Gene therapy vector; Immune responses.
Subjects: Science & Engineering > Biology
Science & Engineering > Institute of Immunology
Item ID: 1749
Identification Number: 10.1099/vir.0.01475-0
Depositing User: Dr. Bernard Mahon
Date Deposited: 15 Dec 2009 11:12
Journal or Publication Title: Journal of General Virology
Publisher: Society of General Microbiology
Refereed: Yes
URI:

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