Interactions between human plasma components and a xenogenic adenovirus vector: reduced immunogenicity during gene transfer.
By the time we are adolescents most of us have been in contact with several of the >50 human adenovirus (HAd) serotypes. These common subclinical infections lead to an efficient anti-adenovirus cross-reacting adaptive immunity. During gene therapy, the ubiquitous anti-adenovirus humoral response and complement activation will modify and dictate vector biodistribution, as well as the response to the virion and transgene(s). In this study, we assayed the interactions of a xenogenic adenovirus derived from canine serotype 2 (CAV-2) with naturally occurring human antibodies (Abs) and the complement system. In our cohort, we found class G immunoglobulins (Igs) that recognized the intact CAV-2 virion and the external virion proteins. However, the majority of donors had low or no neutralizing Abs, class A, or class M Igs. Purified anti-HAd serotype 5 Abs also recognized CAV-2 virion proteins. In addition, in spite of the presence of anti-CAV-2 IgGs, CAV-2 poorly activated the classical and alternative complement cascades. This atypical response was due to a block upstream of the component 3 (C3) convertase and interplay between the component 1 (C1) inhibitor, the C1q-C1r2-C1s2 complex and CAV-2. Our data demonstrate that some xenogenic adenovirus vectors, like CAV-2, could lead to notably different outcomes following systemic delivery.
Perreau
Matthieu
M
Institut de Génétique Moléculaire de Montpellier, Montpellier, France.
Guérin
Marie-Christine
MC
Drouet
Christian
C
Kremer
Eric J
EJ
D000256:Adenoviridae / Q000235:genetics* / Q000276:immunology*; D000917:Antibody Formation / Q000276:immunology; D001798:Blood Proteins / Q000276:immunology* / Q000378:metabolism*; D003429:Cross Reactions; D005822:Genetic Vectors / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D007125:Immunogenetics; D007074:Immunoglobulin G / Q000276:immunology; D037121:Plant Lectins / Q000378:metabolism; D054788:Ribosome Inactivating Proteins / Q000378:metabolism; D015398:Signal Transduction; D014161:Transduction, Genetic
D001798:Blood Proteins; D007074:Immunoglobulin G; D037121:Plant Lectins; C050600:Sambucus nigra lectins; D054788:Ribosome Inactivating Proteins