TNFRs and Control of Chronic LCMV Infection: Implications for Therapy

The control of persistent viral infections requires the immune system to limit the spread of the virus while avoiding immunopathology. Recent studies have revealed that members of the tumor necrosis factor receptor (TNFR) superfamily play unique and pivotal roles in control of chronic lymphocytic choriomeningitis virus (LCMV) infection and in some settings can tip the balance between immune control and immune pathology. We review these findings and discuss how our understanding of the role of TNFRs in the immune response to chronic LCMV infection may shed light on what happens during HIV infection in humans. We discuss preclinical models of TNF/TNFR family-targeted immunotherapy of chronic LCMV infection and evaluate which TNFRs present the most promising targets for immune intervention.

TrendsExpression of several TNFR family members can be induced or sustained on T cells during an immune response, providing NF-κB- and MAPK-mediated pro-survival signals.Recent studies using mice lacking specific TNFRs, or using agonists and blocking antibodies, have revealed non-redundant roles for individual TNFRs in the control of chronic LCMV infections.Transient expression of GITR and OX40 ligands limits signaling via these receptors in chronic infection. GITR and OX40 enhance T cell responses and the control of chronic LCMV infection.Persistent CD27–CD70 signaling results in CD4 T cell and cytokine-mediated destruction of secondary lymphoid organ architecture; blockade of this co-signaling pathway improves control of chronic LCMV.4-1BB has a limited role in control of chronic viral infection owing to degradation of the signaling adaptor TRAF1. IL-7 can restore TRAF1 and enhance the effects of 4-1BB agonists.