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J Virol, March 1998, p. 2388-2397, Vol. 72, No. 3
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Immune Response to Recombinant Capsid Proteins of Adenovirus in Humans: Antifiber and Anti-Penton Base Antibodies Have a Synergistic Effect on Neutralizing Activity

Hanne Gahéry-Ségard,1,* Françoise Farace,2 Dominique Godfrin,1 Jesintha Gaston,1 Renée Lengagne,1 Thomas Tursz,2 Pierre Boulanger,3 and Jean-Gérard Guillet1

Laboratoire d'Immunologie des Pathologies Infectieuses et Tumorales, INSERM Unité 445, Institut Cochin de Génétique Moléculaire, Université R. Descartes, Hôpital Cochin, 75014 Paris,1 Départements de Biologie Clinique ou de Médecine, Institut Gustave Roussy, 94805 Villejuif,2 and Laboratoire de Virologie Moléculaire et Pathogénèse Virale, CNRS-UMR 5812, Faculté de Médecine, 34060 Montpellier,3 France

Received 14 August 1997/Accepted 1 December 1997

Replication-deficient adenovirus used in humans for gene therapy induces a strong immune response to the vector, resulting in transient recombinant protein expression and the blocking of gene transfer upon a second administration. Therefore, in this study we examined in detail the capsid-specific humoral immune response in sera of patients with lung cancer who had been given one dose of a replication-defective adenovirus. We analyzed the immune response to the three major components of the viral capsid, hexon (Hx), penton base (Pb), and fiber (Fi). A longitudinal study of the humoral response assayed on adenovirus particle-coated enzyme-linked immunosorbent assay plates showed that patients had preexisting immunity to adenovirus prior to the administration of adenovirus-beta -gal. The level of the response increased in three patients after adenovirus administration and remained at a maximum after three months. One patient had a strong immune response to adenovirus prior to treatment, and this response was unaffected by adenovirus administration. Sera collected from the patients were assayed for recognition of each individual viral capsid protein to determine more precisely the molecular basis of the humoral immune response. Clear differences existed in the humoral response to the three major components of the viral capsid in serum from humans. Sequential appearance of these antibodies was observed: anti-Fi antibodies appeared first, followed by anti-Pb antibodies and then by anti-Hx antibodies. Moreover, anti-Fi antibodies preferentially recognized the native trimeric form of Fi protein, suggesting that they recognized conformational epitopes. Our results showed that sera with no neutralizing activity contained only anti-Fi antibodies. In contrast, neutralizing activity was only obtained with sera containing anti-Fi and anti-Pb antibodies. More importantly, we showed that anti-native Fi and anti-Pb antibodies had a synergistic effect on neutralization. The application of these conclusions to human gene therapy with recombinant adenovirus should lead to the development of strategies to overcome the formation of such neutralization antibodies, which have been shown to limit the efficacy of gene transfer in humans.

* Corresponding author. Mailing address: Laboratoire d'Immunologie des Pathologies Infectieuses et Tumorales, INSERM Unité 445, Institut Cochin de Génétique Moléculaire, Hôpital Cochin, 27 rue du Fg Saint Jacques, 75014 Paris, France. Phone: 33 1 46334395. Fax: 33 1 44071425. E-mail: gahery{at}icgm.cochin.inserm.fr.




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