Persistent viral infections are a major health concern. One obstacle inhibiting the clearance of persistent infections is functional inactivation of antiviral T cells. Although such immunosuppression occurs rapidly after infection, the mechanisms that induce the loss of T-cell activity and promote viral persistence are unknown. Herein we document that persistent viral infection in mice results in a significant upregulation of interleukin (IL)-10 by antigen-presenting cells, leading to impaired T-cell responses. Genetic removal of Il10 resulted in the maintenance of robust effector T-cell responses, the rapid elimination of virus and the development of antiviral memory T-cell responses. Therapeutic administration of an antibody that blocks the IL-10 receptor restored T-cell function and eliminated viral infection. Thus, we identify a single molecule that directly induces immunosuppression leading to viral persistence and demonstrate that a therapy to neutralize IL-10 results in T-cell recovery and the prevention of viral persistence.

Type I interferons (IFN-I) are critical for antiviral immunity; however, chronic IFN-I signaling is associated with hyperimmune activation and disease progression in persistent infections. We demonstrated in mice that blockade of IFN-I signaling diminished chronic immune activation and immune suppression, restored lymphoid tissue architecture, and increased immune parameters associated with control of virus replication, ultimately facilitating clearance of the persistent infection. The accelerated control of persistent infection induced by blocking IFN-I signaling required CD4 T cells and was associated with enhanced IFN-γ production. Thus, we demonstrated that interfering with chronic IFN-I signaling during persistent infection redirects the immune environment to enable control of infection.

CD4 + and CD8 + T cell functions are rapidly aborted during chronic infection, preventing viral clearance. CD4 + T cell help is required throughout chronic infection so as to sustain CD8 + T cell responses; however, the necessary factor(s) provided by CD4 + T cells are currently unknown. Using a mouse model of chronic viral infection, we demonstrated that interleukin-21 (IL-21) is an essential component of CD4 + T cell help. In the absence of IL-21 signaling, despite elevated CD4 + T cell responses, CD8 + T cell responses are severely impaired. CD8 + T cells directly require IL-21 to avoid deletion, maintain immunity, and resolve persistent infection. Thus, IL-21 specifically sustains CD8 + T cell effector activity and provides a mechanism of CD4 + T cell help during chronic viral infection.During chronic viral infections, antiviral CD4 + and CD8 + T cells become non-responsive to viral antigens and are either physically deleted or persist in a nonfunctional "exhausted" state, unable to produce important antiviral and immunostimulatory cytokines such as interleukin-2 (IL-2), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ); lyse virally infected cells; or proliferate (1-4). To date, the majority of work analyzing T cell exhaustion during chronic viral infection has focused on CD8 + T cells; however, CD4 + T cells also exhibit reduced function, thus further exacerbating viral persistence. CD4 + T cells are required throughout chronic viral infection in order to sustain CD8 + T cell function and control infection, prevent deletion of high-affinity antiviral CD8 + T cells, and eventually resolve the infection (5-7). The loss of CD4 + and CD8 + T cell function is associated with viruses that establish chronic viral infections in their hosts: HIV and hepatitis B and hepatitis C virus (HCV) in humans and lymphocytic chorio-meningitis virus (LCMV) in rodents (8)(9)(10)(11)(12). Chronic LCMV infection is eventually controlled in the periphery 60 to 80 days after infection in a CD4 + T cell-dependent manner, suggesting that exhausted CD4 + T cells retain helper activity. Expression of the key CD4 + T cell helper cytokine IL-2, however, is rapidly extinguished during viral persistence (4,13), indicating that an alternative helper mechanism is being implemented.To determine how CD4 + T cells help CD8 + T cells to clear a viral infection, we infected mice with the Armstrong strain of LCMV (Arm) that induces a robust T cell response, resulting in viral clearance within 8 to 10 days or with the Clone 13 strain of LCMV (Cl 13) that generates a chronic infection due to the up-regulation of immunosuppressive factors that induce a dramatic depletion and inactivation of virus-specific T cells (14-18). LCMV-Arm and -Cl 13 share identical CD4 + and CD8 + T cell epitopes, enabling direct comparison of