Inactivation of antiviral T cells is a key obstacle preventing the clearance of persistent infections by a wide range of viruses, including HIV, hepatitis B virus (HBV) and hepatitis C virus (HCV) in humans, and lymphocytic choriomenigitis virus (LCMV) in rodents. However, the mechanisms that initially induce immunosuppression and lead to viral persistence are unclear. Now, two papers report that interleukin-10 (IL-10) has an important role in this process, and provide evidence that IL-10 blockade might have therapeutic potential for chronic viral infections.

To determine the mechanism by which viruses induce immunosuppression, both Brooks and colleagues writing in Nature Medicine, and Ejrnaes and colleagues writing in the Journal of Experimental Medicine, used mice infected with LCMV clone 13 (LCMV13), which results in a chronic infection associated with impairment and deletion of virus-specific CD8+ T cells.

Brooks and colleagues observed increased IL-10 RNA in the spleens of LCMV13-infected mice, and the increased IL-10 production potentiated T-cell inactivation. However, in IL-10-deficient LCMV13-infected mice, there were increased numbers of virus-specific T cells, and no infectious virus could be isolated 9 or 42 days following infection. No increased immunopathology, nor increased levels of neutralizing antibodies were associated with the rapid viral clearance in these mice.

IL-10-deficient mice previously infected with LCMV13 were also resistant to re-infection after viral rechallenge, indicating the development of competent memory T-cell responses. Furthermore, antibody blockade of IL-10 after the establishment of infection increased numbers of virus-specific T cells and sustained T-cell activity, decreased viral titres, and in one case resulted in clearance of the virus.

Ejrnaes and colleagues also showed that infection with LCMV13 resulted in increased IL-10 production in splenocytes, and suggested that the immune suppression mediated by LCMV13 was caused by a shift from antiviral interferon-γ (IFNγ) production to the secretion of immunosuppressive IL-10.

The use of an antibody against IL-10 in LCMV13-infected mice resulted in low LCMV genomic-copy numbers and was effective during established infection, when it was able to reverse lymphopaenia. Anti-IL-10 treatment resulted in a potent antiviral IFNγ-secreting CD8+ T-cell response, and decreased expression of programmed death 1 (PD1) on T cells, which has recently been identified as having a key role in sustaining suppression of CD8+ T cells during persistent infection.

Elevated levels of IL-10 are observed during human HIV, HBV and HCV infections, and correlate with reduced T-cell activity and failure to control viral replication. Therefore, these two papers raise the possibility that IL-10 blockade might enhance the treatment of these persistent infections. And importantly, given that such a strategy is targeting a host factor that does not directly interact with the virus, it is unlikely that resistance owing to viral mutation would emerge, which is a cause of many treatment failures with current drugs.