In addition to neutralization, antibodies are also able to mediate their antiviral activity through the recruitment of innate immune cell activity and complement. Over the past 2 decades, several reports have suggested that these innate immune recruiting antibodies may play a role in durable control of infection in long‐term non‐progressors, and recently several groups have begun to speculate that these antibody functions may have provided some transient protection against infection in the RV144 vaccine trial. However the signals required to induce these innate immune recruiting antibodies have been poorly characterized. Interestingly, B cells represent an important evolutionary link between the adaptive and innate immune systems, as they express both an antigen specific B‐cell receptor (BCR) and a variety of innate immune sensing receptors, including Toll‐like receptors (TLRs). New evidence suggest that B cells express unique patterns of TLRs at different steps in their maturation process, and that in addition to TLR potentiation of the BCR signal, TLRs may also help a B cell to determine the microbial origin of antigens recognized by the BCR allowing it to tailor its antibody response to the infectious agents. Thus TLRs may modulate the BCR response during infection to fine‐tune the quality of antibodies. Previous work has shown that chronic inflammation is associated with the induction of antibodies with reduced capacity to mediate antibody‐dependent cellular cytotoxicity (ADCC), related to changes in the glycan attached to the antibody heavy chain. Furthermore, these glycan structures can be modulated following B cell stimulation with different inflammatory cytokines, suggesting that this glycan can be manipulated through different stimuli. Furthermore, preliminary data from our group strongly suggest that distinct TLRs are able to modulate the glycosyltransferase profile within memory B cells and B cell lines, and result in the generation of antibodies with altered glycans that enhance their affinity for specific Fc‐receptors. Given these exciting new observations, it is conceivable that defining innate immune signals on B cells that are able to induce the production of enhanced ADCC inducing antibodies may provide a unique opportunity to translate these findings to promote the production of ADCC inducing antibodies to prevent or slow HIV disease progression.
In this proposal we intend to dissect the innate immune danger signals, elicited by pattern recognition receptors, on B cells that drive the induction of innate immune recruiting antibodies, such as those that mediate ADCC, that may be critical for antiviral control of HIV infection.
