Activation of a dendritic cell–T cell axis by Ad5 immune complexes creates an improved environment for replication of HIV in T cells

Author:

Perreau Matthieu1,Pantaleo Giuseppe12,Kremer Eric J.34

Affiliation:

1. Service of Immunology and Allergy, Department of Medicine, Centre Hospitalier, Universitaire Vaudois, Lausanne, University of Lausanne, CH-1011 Lausanne, Switzerland

2. Swiss Vaccine Research Institute, 1011 Lausanne, Switzerland

3. Institut de Génétique Moléculaire de Montpellier, Centre National de la Recherche Scientifique 5535, 34293 Montpellier, France

4. Université Montpellier I and II, 34967 Montpellier, France

Abstract

The STEP HIV vaccine trial, which evaluated a replication-defective adenovirus type 5 (Ad5) vector vaccine, was recently stopped. The reasons for this included lack of efficacy of the vaccine and a twofold increase in the incidence of HIV acquisition among vaccinated recipients with increased Ad5-neutralizing antibody titers compared with placebo recipients. To model the events that might be occurring in vivo, the effect on dendritic cells (DCs) of Ad5 vector alone or treated with neutralizing antiserum (Ad5 immune complexes [IC]) was compared. Ad5 IC induced more notable DC maturation, as indicated by increased CD86 expression, decreased endocytosis, and production of tumor necrosis factor and type I interferons. We found that DC stimulation by Ad5 IC was mediated by the Fcγ receptor IIa and Toll-like receptor 9 interactions. DCs treated with Ad5 IC also induced significantly higher stimulation of Ad5-specific CD8 T cells equipped with cytolytic machinery. In contrast to Ad5 vectors alone, Ad5 IC caused significantly enhanced HIV infection in DC–T cell cocultures. The present results indicate that Ad5 IC activates a DC–T cell axis that, together with the possible persistence of the Ad5 vaccine in seropositive individuals, may set up a permissive environment for HIV-1 infection, which could account for the increased acquisition of HIV-1 infection among Ad5 seropositive vaccine recipients.

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

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