Endogenous cytotoxic T-cell response contributes to the long-term antiretroviral protection induced by a short period of antibody-based immunotherapy of neonatally infected mice

Neutralizing monoclonal antibodies (MAbs) are increasingly being considered for blunting human viral infections. However, whether they can also exert indirect effects on endogenous antiviral immune responses has been essentially overlooked. We have recently shown that a short (several-day) period of immunotherapy with the neutralizing 667 MAb of mouse neonates shortly after infection with the lethal FrCas(E) retrovirus not only has an immediate effect on the viral load but also permits an endogenous antiviral immunity to emerge. Even though passive immunotherapy was administered during the particular period of immunocompetence acquisition, the endogenous response eventually arising was protective and persisted long (>1 year) after the MAb has disappeared. As very high levels of anti-FrCas(E) antibodies, predominantly of the immunoglobulin G2a (IgG2a) isotype and showing strong neutralization activity, were found in the sera of MAb-treated mice, it was necessary to address whether this humoral immunity was sufficient on its own to confer full protection against FrCas(E) or whether a cytotoxic T-lymphocyte (CTL) response was also necessary. Using a variety of in vivo assays in young and adult animals previously infected by FrCas(E) and treated by 667, we show here that transient 667 immunotherapy is associated with the emergence of a CTL response against virus-infected cells. This cytotoxic activity is indispensable for long-term antiviral protective immunity, as high neutralizing antibody titers, even enhanced in in vivo CD8(+) cell depletion experiments, cannot prevent the FrCas(E)-induced death of infected/treated mice. Our work may have important therapeutic consequences, as it indicates that a short period of MAb-based immunotherapy conducted at a stage where the immune system is still developing can be associated with the mounting of a functional Th1-type immune response characterized by both CTL and IgG2a-type humoral contributions, the cooperation of which is known to be essential for the containment of chronic infections by a variety of viruses.