Long-term immune control of viral replication still remains a major challenge in retroviral diseases. Several monoclonal antibodies (MAbs) have already shown antiviral activities in vivo, including in the clinic but their effects on the immune system of treated individuals are essentially unknown. Using the lethal neurodegeneration induced in mice upon infection of neonates by the FrCas E retrovirus as a model, we report here that transient treatment by a neutralizing MAb shortly after infection can, after an immediate antiviral effect, favor the development of a strong protective host immune response containing viral propagation long after the MAb has disappeared. In vitro virus neutralization-and complement-mediated cell lysis assays, as well as in vivo viral challenges and serum transfer experiments, indicate a clear and essential contribution of the humoral response to antiviral protection. Our observation may have important therapeutic consequences as it suggests that short antibody-based therapies early after infection should be considered, at least in the case of maternally infected infants, as adjunctive treatment strategies against human immunodeficiency virus, not only for a direct effect on the viral load but also for favoring the emergence of an endogenous antiviral immune response.The therapeutic use of monoclonal antibodies (MAbs) has increased spectacularly in recent years (10,26,27). It now concerns a wide range of diseases with 13 MAbs approved for human use by the Food and Drug Administration and more than 400 others currently tested in clinical trials (27), including the treatment of chronic viral diseases such as hepatitis B virus (15,20), hepatitis C virus (15) and human immunodeficiency virus (4, 11, 59) infections. Due to their potential in the treatment of AIDS, several human immunodeficiency virus-neutralizing MAbs have already been obtained and studied (22,23,53) and others are being generated by various laboratories worldwide.Some of the available MAbs have already shown antiviral activity in vivo in a variety of adult and neonatal animal and human settings (see Discussion). Immediate antiviral effects in these experiments were due to direct virus neutralization. However, whether short-term MAb-based immunotherapies could, in addition, favor the emergence of endogenous antiviral immune responses contributing to the protection of infected individuals in the long term has hardly been considered thus far. As the elucidation of fundamental concepts in retroviral immunology is easier to attain in immunocompetent mouse models than in humans or monkeys, we turned to the neonatal infection system by the FrCas E retrovirus to address this issue. This model constitutes an invaluable tool to address the development of a protective immune response during the critical period of immunocompetence acquisition in young organisms, a situation which is reminiscent of that of perinatal infant infection by human immunodeficiency virus.FrCas E is an ecotropic mouse retrovirus (50). Upon inoculation to newbo...