High levels of foreign antigens associated with virus infection are thought to drive germinal center formation and antigen-specific B cell development. induction of splenic germinal center B cells and plasmablasts during acute FV contamination. 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. INTRODUCTION The biological outcome of Friend retrovirus (FV) contamination of mice is usually dictated by multiple resistance and susceptibility genes (1, 2). FV contamination of mouse strains such as A.BY and BALB/c results in the polyclonal activation of erythroblast precursors that leads to severe splenomegaly and erythroleukemia. On the other hand, mouse strains such as C57BL/6 (B6) are resistant to splenomegaly due to the absence of a dominant susceptibility gene Rabbit Polyclonal to VE-Cadherin (phospho-Tyr731) (3, 4). FV disease is also alleviated in certain mouse strains by the development of potent cell-mediated and humoral immune responses, both of which map to specific genetic loci. Cell-mediated immune responses are primarily controlled by the major histocompatibility complex (locus) (5), while the neutralizing antibody response against FV is usually significantly influenced by a single autosomal dominant gene known as (6). resistant strains such as B6 produce stronger PRT-060318 neutralizing antibody responses compared to susceptible strains (A.BY, BALB/c), and this phenotype maps to a 60-gene region on chromosome 15 based on three consecutive studies of recombinant inbred mice (7C9). We recently provided evidence that is encoded by an innate restriction PRT-060318 factor known as (10). This conclusion was based on our demonstration that genetic inactivation of which is located within the 60-gene region on chromosome 15, reproduced the phenotype of an susceptibility allele. Thus, (B6 encodes a deoxycytidine deaminase that, when incorporated into budding retroviral particles, can render these virions non-infectious in the next target cell [as reviewed in (11)]. Apobec3 can physically impede reverse transcription by its inherent binding to viral RNA (12, 13), deaminate deoxycytidines in single-stranded DNA due to its enzymatic activity resulting in lethal G-to-A hypermutation in the viral plus strand (14C17), and/or impair viral integration through the formation of aberrant cDNA ends (18, 19). susceptible mouse strains (A.BY, BALB/c) exhibit decreased mRNA expression (20, 21), aberrant mRNA splicing of exon 2 (10), reduced mRNA induction following contamination (2) and destabilizing amino acid polymorphisms (21, 22) that altogether, could compromise Apobec3 function. In addition, the alternatively spliced Apobec3 exon5 variant in the resistant B6 strain was also shown to have stronger antiviral activity than full-length Apobec3 (21, 22). Thus, a combination of these Apobec3 polymorphisms likely explains why Apobec3 is usually more potent in resistant (B6) versus susceptible (BALB/c, A.BY) strains. However, the underlying mechanism by which Apobec3 influences the adaptive immune response resulting in effective FV-specific neutralizing antibody responses remains unknown. We previously proposed that the ability of Apobec3/to influence the FV-specific neutralizing antibody response could be due either to a direct or indirect mechanism of action (10). Apobec3 is usually evolutionarily related to activation-induced deaminase (AID) (23), an enzyme expressed in B cells that facilitates class-switching and affinity maturation of antibodies (24). Thus, it is plausible that Apobec3 present in B cells could influence antibody development by supplementing PRT-060318 AID function mechanism of Apobec3 action, where the development of neutralizing antibody responses are augmented as a result of Apobec3-mediated reduction in virus-induced pathology during the acute phase of contamination. To distinguish between these possibilities, we performed immunization studies in mice using a.