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One of the most profound enigmas in B cell biology is how activation-induced deaminase (AID) is targeted to a very small region of DNA in the immunoglobulin loci. Two specific regions are singled out: the variable region of 2 kb that contains rearranged genes on the heavy, κ light, and λ light chain loci, and the switch region of ∼4 kb that contains an extensive stretch of G:C rich DNA on the heavy chain locus. Transcription is required for AID recruitment; however, many genes are also highly transcribed and do not undergo the catastrophic mutagenesis that occurs in variable and switch regions. The DNA sequences of these regions cause RNA polymerase II to accumulate for an extended distance of 2–4 kb. The stalled polymerases then recruit the transcription cofactor Spt5, and AID, which deaminates cytosines to uracils in exposed transcription bubbles. Thus, the immunoglobulin loci are unique in that a favorable combination of DNA sequences and 3′ transcription enhancers make them the perfect storm for AID-induced somatic hypermutation.

Acute viral infections are characterized by rapid increases in viral load, leading to cellular damage and the resulting induction of complex innate and adaptive antiviral immune responses that cause local and systemic inflammation. Successful antiviral immunity requires the activation of many immune cells, including T cells, natural killer cells, and macrophages. B cells play a unique part through their production of antibodies that can both neutralize and clear viral particles before virus entry into a cell. Protective antibodies are produced even before the first exposure of a pathogen, through the regulated secretion of so-called natural antibodies that are generated even in the complete absence of prior microbial exposure. An early wave of rapidly secreted antibodies from extrafollicular (EF) responses draws on the preexisting naive or memory repertoire of B cells to induce a strong protective response that in kinetics tightly follows the clearance of acute infections, such as with influenza virus. Finally, the generation of germinal centers (GCs) provides long-term protection through production of long-lived plasma cells and memory B cells, which shape and broaden the B cell repertoire for more effective responses following repeat exposures. In this study, we review B cell responses to acute viral infections, primarily influenza virus, from the earliest nonspecific B-1 cell to early, antigen-specific EF responses and finally to GC responses. Throughout, we address known factors that lead to distinct B cell response outcomes and discuss how their functions effect viral clearance, highlighting the critical contributions of each response type to the induction of highly protective antiviral humoral immunity.

Adaptive antibody responses provide a crucial means of host defense against viral infections by mediating the neutralization and killing infectious pathogens. At the forefront of humoral defense against viruses lie a subset of innate-like serum antibodies known as natural antibodies (NAbs). NAbs serve multifaceted functions in host defense and play an essential role in early immune responses against viruses. However, there remain many unanswered questions with regard to both the breadth of viral antigens recognized by NAbs, and how B cell ontology and individual antigenic histories intersect to control the development and function of antiviral human NAbs. In the following article we briefly review the current understanding of the functions and source of NAbs in the immune repertoire, their role during antiviral immune responses, the factors influencing the maturation of the NAb repertoire, and finally, the gaps and future research needed to advance our understanding of innate-like B cell biology for the purpose of harnessing NAbs for host defense against viral infections.