Combining Regulatory T Cell Depletion and Inhibitory Receptor Blockade Improves Reactivation of Exhausted Virus-Specific CD8+ T Cells and Efficiently Reduces Chronic Retroviral Loads

Chronic infections with human viruses,such as hiv and hcv,or mouse viruses,such as lcmv or friend virus (fv),result in functional exhaustion of cd8+ t cells. two main mechanisms have been described that mediate this exhaustion: expression of inhibitory receptors on cd8+ t cells and expansion of regulatory t cells (tregs) that suppress cd8+ t cell activity. several studies show that blockage of one of these pathways results in reactivation of cd8+ t cells and partial reduction in chronic viral loads. using blocking antibodies against pd-1 ligand and tim-3 and transgenic mice in which tregs can be selectively ablated,we compared these two treatment strategies and combined them for the first time in a model of chronic retrovirus infection. blocking inhibitory receptors was more efficient than transient depletion of tregs in reactivating exhausted cd8+ t cells and reducing viral set points. however,a combination therapy was superior to any single treatment and further augmented cd8+ t cell responses and resulted in a sustained reduction in chronic viral loads. these results demonstrate that tregs and inhibitory receptors are non-overlapping factors in the maintenance of chronic viral infections and that immunotherapies targeting both pathways may be a promising strategy to treat chronic infectious diseases. © 2013 dietze et al.