Natural exposure to AAV-2 in 45 healthy donors resulted in 41 being seropositive, with robust cell-mediated immune responses directed against 59 candidate T-cell epitopes of the VP1 capsid protein.
Cross-Sectional (n=45)
Robust immunological memory to AAV-2 is established in humans, with diverse T-cell epitopes recognized, suggesting that modifying the AAV-2 capsid to avoid immunity may not be feasible.
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-gamma) (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.
Madsen et al. (Fri,) conducted a cross-sectional in Healthy blood donors (n=45). AAV-2 exposure was evaluated on AAV-2-specific total IgG levels and cell-mediated immune recall responses. Natural exposure to AAV-2 in 45 healthy donors resulted in 41 being seropositive, with robust cell-mediated immune responses directed against 59 candidate T-cell epitopes of the VP1 capsid protein.