Innate retroviral restriction by Apobec3 promotes antibody affinity maturation in vivo1

• Published in: The Journal of immunology (1950) Vol. 185; no. 2; pp. 1114 - 1123
• Main Authors: Santiago, Mario L., Benitez, Robert L., Montano, Mauricio, Hasenkrug, Kim J., Greene, Warner C.
• Format: Journal Article
• Language: English
• Published: 21.06.2010
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1001143

Apobec3/ Rfv3 is an innate immune factor that promotes the neutralizing antibody response against Friend retrovirus (FV) in infected mice. Based on its evolutionary relationship to activation-induced deaminase (AID), Apobec3 might directly influence antibody class switching and affinity maturation independently of viral infection. Alternatively, the antiviral activity of Apobec3 may indirectly influence neutralizing antibody responses by reducing early FV-induced pathology in critical immune compartments. To distinguish between these possibilities, we immunized wild-type and Apobec3-deficient C57BL/6 (B6) mice with (4-hydroxy-3-nitrophenyl) acetyl (NP) hapten and evaluated the binding affinity of the resultant NP-specific antibodies. These studies revealed similar affinity maturation of NP-specific IgG1 antibodies between wild-type and Apobec3 deficient mice in the absence of FV infection. In contrast, hapten-specific antibody affinity maturation was significantly compromised in Apobec3-deficient mice infected with FV. In highly susceptible (B6 x A.BY)F 1 mice, the B6 Apobec3 gene protected multiple cell types in the bone marrow and spleen from acute FV infection including erythroid, B, T and myeloid cells. In addition, B6 Apobec3 deficiency was associated with elevated immunoglobulin levels but decreased induction of splenic germinal center B cells and plasmablasts during acute FV infection. These data suggest that Apobec3 indirectly influences FV-specific neutralizing antibody responses by reducing virus-induced immune dysfunction. These findings raise the possibility that enabling Apobec3 activity during acute infection with human pathogenic retroviruses such as HIV-1 may similarly facilitate stronger virus-specific neutralizing antibody responses.