1. ¹Institut de Génétique Moléculaire de Montpellier, Montpellier, France
2. ²CNRS—Universities of Montpellier I and II, Montpellier, France
3. ³Laboratoire d'Immunologie, Université Joseph Fourier Grenoble 1 and CHU Grenoble, Grenoble, France

Correspondence: Eric J. Kremer, IGMM CNRS 5535, 1919 Route de Mende, 34293 Montpellier, France. E-mail: eric.kremer@igmm.cnrs.fr

^*Present address: National Centre for Angioedema, CHU Grenoble and Université Joseph Fourier, TIMC-IMAG, CNRS UMR 5525, 38043 Grenoble, France.

Received 3 April 2007; Accepted 23 July 2007; Published online 21 August 2007.

Abstract

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.