114 : Interferon-alpha therapy enhances the anti-friend virus B cell response through Apobec3

Abstract

Therapeutic administration of IFN- α in clinical trials significantly reduced HIV-1 plasma viral load and HTLV-I proviral load in infected patients. However, the downstream antiretroviral effector(s) of IFN- α therapy remain unknown. Here we use the mouse Friend virus (FV) infection model to interrogate a potential effector protein, Apobec3. Lab and wild strains of mice have one of two forms of Apobec3, one associated with greater resistance to Friend Retrovirus ( Rfv3 r ) and improved neutralizing antibody titers, and one associated with greater susceptibility ( Rfv3 s ). We previously showed that in B6 mice, which are Rfv3 r / r , IFN- α treatment inhibits acute FV infection primarily through Apobec3 in vivo. This raised the question of whether IFN-therapy could be effective in an Rfv3 s / s mouse strain. Additionally, we asked if IFN-treatment could therapeutically improve neutralizing antibody responses through Apobec3. Here we show that an IFN- α treatment regimen potently restricts acute FV in the Rfv3 s / s 129 mouse strain independently of Apobec3, suggesting that different IFN-effectors may have evolutionarily gained potency in the absence of resistant Apobec3. However, IFN- α efficacy in later infection was dependent on Apobec3, and was associated with an increase in FV-reactive IgG2a. The increase in FV-reactive IgG2a was associated with an Apobec3-dependent B cell response characterized by increased germinal center and plasmablast formation. These data show that even the weak form of Apobec3 stimulates an enhanced B cell response during IFN-therapy, which confirms the potential of the IFN-Apobec3 axis as an antiretroviral therapeutic target or vaccine adjuvant.