Using FrCas(E) retrovirus-infected newborn mice as a model system, we have shown recently that a long-lasting antiviral immune response essential for healthy survival emerges after a short treatment with a neutralizing (667) IgG2a isotype monoclonal antibody (MAb). This suggested that the mobilization of adaptive immunity by administered MAbs is key for the success in the long term for the MAb-based passive immunotherapy of chronic viral infections. We have addressed here whether the anti-FrCas(E) protective endogenous immunity is the mere consequence of viral propagation blunting, which would simply give time to the immune system to react, and/or to actual immunomodulation by the MAb during the treatment. To this aim, we have compared viral replication, disease progression, and antiviral immune responses between different groups of infected mice: (i) mice treated with either the 667 MAb, its F(ab’)(2) fragment, or an IgM (672) with epitopic specificity similar to that of 667 but displaying different effector functions, and (ii) mice receiving no treatment but infected with a low viral inoculum reproducing the initial viral expansion observed in their infected/667 MAb-treated counterparts. Our data show that the reduction of FrCas(E) propagation is insufficient on its own to induce protective immunity and support a direct immunomodulatory action of the 667 MAb. Interestingly, they also point to sequential actions of the administered MAb. In a first step, viral propagation is exclusively controlled by 667 neutralizing activity, and in a second one, this action is complemented by FcgammaR-binding-dependent mechanisms, which most likely combine infected cell cytolysis and the modulation of the antiviral endogenous immune response. Such complementary effects of administered MAbs must be taken into consideration for the improvement of future antiviral MAb-based immunotherapies.
Long-lasting protective antiviral immunity induced by passive immunotherapies requires both neutralizing and effector functions of the administered monoclonal antibody
Nasser, R.; Pelegrin, M.; Michaud, H. A.; Plays, M.; Piechaczyk, M.; Gros, L.
2010-10 / vol 84 / pages 10169-81
10.1128/JVI.00568-10 JVI.00568-10 [pii]
1098-5514 (Electronic) 0022-538X (Linking)
Animals; Mice; Amino Acid Sequence; Molecular Sequence Data; Disease Models, Animal; Animals, Newborn; *Immunization, Passive; Antibodies, Monoclonal/*administration & dosage/chemistry; Antibodies, Neutralizing/*administration & dosage/chemistry; Antibodies, Viral/*administration & dosage/chemistry; Antigens, Viral/genetics; CD8-Positive T-Lymphocytes/immunology; Epitopes/genetics; Friend murine leukemia virus/genetics/pathogenicity/physiology; Immunoglobulin Fc Fragments/administration & dosage/chemistry; Leukemia, Experimental/immunology/prevention & control/therapy; Retroviridae Infections/*immunology/prevention & control/*therapy; Retroviridae/genetics/pathogenicity/physiology; Tumor Virus Infections/immunology/prevention & control/therapy; Viral Envelope Proteins/genetics/immunology; Virus Replication/immunology