In 2016 the Retroviral Immunology Section continued investigation into host mechanisms of genetic resistance and susceptibility to retroviral infection. These findings have implications for the design of therapeutics and vaccines to treat and prevent infections with viruses such as HIV. Studies of Friend retrovirus-infected mice revealed significant increases in polyreactive antibodies following acute infection. Polyreative antibodies are a major component of natural antibodies that form a first line of defense against bacteria and viruses. In collaboration with Abner Notions we investigated the mechanisms that trigger the induction of polyreactive antibodies. These studies revealed a dependence of TLR-mediated pathogen recognition and signaling via MyD88. Furthermore, we demonstrated that as much as half of the IgM in serum is polyreactive, and that some of these antibodies are precursors to high affinity antibodies of the adaptive immune system (Gunti et al. 2015). Another important part of immunity to acute retroviral infections is the immediate responses of the intrinsic immune system, of which restriction factors play a major role. One such factor is Tetherin/BST-2, which was known to restrict HIV in vitro, but it's role in vivo has not been studied. In collaboration with Mario Santiago we used Friend virus infections of mice as a model to determine the effects of Tetherin in vivo. Interestingly, Tetherin enhanced myeloid dendritic cell (DC) function. DCs from infected, but not uninfected, WT mice expressed significantly higher MHC class II and the co-stimulatory molecule CD80 compared to Tetherin KO DCs. Tetherin-associated DC activation during acute FV infection correlated with stronger NK cell responses. Furthermore, Tetherin+ DCs from FV-infected mice more strongly stimulated FV-specific CD4+ T cells ex vivo compared to Tetherin KO DCs. The results link the antiretroviral and immunomodulatory activity of Tetherin in vivo to improved DC activation and MHC class II antigen presentation ( Li et al. 2016). Our studies delineating the mechanisms of protection by live attenuated retroviral vaccines led to a collaboration with William Halford who spent several months in my lab adapting our techniques to the study of a live-attenuated Herpes simplex virus 2 (HSV-2) vaccine. These studies showed that the DeltaNLS mutant vaccine strain was safe, even in highly immunodeficient mice, and that it provided extremely potent (100%) protection from high doses of challenge in terms of both virus shedding and protection from pathology. The vaccine induced both T cell and B cell responses and studies and B cell deficient mice combined with passive antibody studies revealed a critical role for virus-specific antibodies in vaccine-induced protection against HSV-2 (Halford 2015).
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