PROJECT SUMMARY/ABSTRACT The goal of this application is to identify novel mechanisms by which antiretroviral antibody responses are generated. Retroviruses are highly successful pathogens, able to subvert or evade immune responses in most infected individuals. In some unique cases, the detection of viral infection by the innate immune system results in the induction of an adaptive immune response able to control viral infection and prevent the development of disease. This ability to control retroviral replication is most often driven by the specific genetic make-up of the host. However, investigation of the genetic and immunologic basis for these responses in humans is extremely difficult; therefore, animal models of retroviral infection are required for the dissection of the requirements for protective immune responses. To this end, murine models of retroviral infection have provided essential insights into understanding the molecular mechanisms of anti-retroviral immune responses. In particular, inbred strains capable of mounting neutralizing antibody responses provide the opportunity to dissect the signaling pathways underlying these responses. The canonical pathway for antiviral antibody production in mice involves detection of retroviral RNA in the endosome by the innate immune receptor Toll-like receptor 7 (TLR7). TLR7/MyD88 signaling is followed by activation of CD4+ T cells, and IFNγ-mediated stimulation of Ab production by virus- specific B cells. This is the predominant pathway for the generation of neutralizing responses to a variety of RNA virus infections, including retroviral infections. We recently identified that some inbred mice inherit an alternative, TLR7-independent pathway to produce retrovirus-neutralizing antibodies. The studies proposed in this application will elucidate (1) the genetic mechanisms underlying this unique pathway, and (2) the alternative innate immune mechanism that stimulates this alternative pathway. The knowledge gained by this investigation will uncover the basis for a previously unappreciated pathway for antibody production in response to viral infection. Such insight could greatly aid the development of new animal models of human disease and novel therapeutic intervention.