Although it has been widely observed in the field, there are few reports in the literature about the mechanism and prevalence of antibody-dependent enhancement of AAV. One paper has observed that mouse anti-AAV2 antiserum is capable of enhancing transduction in monocytic cell lines such as THP-1 and U937, and that blocking FcγRI and FcγRII with anti-FcγRI and FcγRII antibodies decreases this enhancement (275). Enhancement has also been observed in mouse bone marrow macrophages in the presence of mouse serum from mice pre-immunized with AAV2 (276). This group determined that enhancement in these cell lines was due to complement protein C3, as recombinant C3 can bind to AAV2 capsids and heat inactivation abrogated this effect. These two reports, although supporting the ability of AAV to undergo enhancement, do little to define the mechanism of enhancement observed in non-immune cells and whether this enhancement occurs in vivo. For other viruses, enhancement has been reported to occur either through the Fc receptor mediating uptake into immune cells for viruses such as Dengue virus (277, 278), or complement-bound antibodies mediating entry into non-immune cells such as Ebola (279) and Parvovirus B19 (280). This is observed in situations where there are low affinity antibodies, such as during secondary infection with a different serotype than the primary infection (281). We have observed enhancement in vitro of up to 10-fold from serum samples that are neutralizing against other AAV serotypes. By understanding more about the mechanisms by which sub- detectable levels of antibodies affect transduction, we can develop methods to circumvent their activity in ways that are translatable to the clinic. We have used both in vitro and in vivo studies in mice in an attempt to dissect the role anti-AAV antibodies are playing in AAV entry outside of a classical neutralization mechanism.
Adapted From:
A Genome-Wide Knock-Out Screen Identifies Novel Host Cell Entry Factor Requirements for Divergent Adeno-Associated Virus Serotypes. A dissertation presented by Amanda Mary Dudek, Harvard University, September 2018.
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