Genetic basis for interferon-gamma-independent antiviral antibody production

= 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. 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 stimulation of antigen- specific B cells by the cytokine interferon-γ (IFNγ), resulting in production of virus specific antibodies of the IgG2a isotype. This is the predominant pathway for the generation of neutralizing responses to a variety of viral infections, including retroviral infections. We recently identified that some inbred mice inherit an alternative, IFNγ- independent pathway to produce retrovirus-neutralizing IgG2a antibodies. The mechanism of resistance is recessive and controlled by a single locus in which we have identified a candidate gene. The studies proposed in this application will elucidate the genetic mechanisms underlying this unique 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.