UCLA

Persistent virus infections are a significant burden on global health with over 500 million people afflicted with human immunodeficiency virus (HIV), and hepatitis B and C viruses combined. These viruses rapidly replicate and achieve elevated virus loads that are sustained for extended periods of time, often for the life of the host. An unchecked immune response against uncontrollable virus replication will almost certainly lead to deadly immunopathology. Therefore, the insurmountable levels of virus and the continual inflammation that results therefrom act to induce potent host-derived immunosuppressive programs. In the effort to prevent immunopathology, the prolonged activity of immunosuppressive programs deteriorates or diverts effective anti-viral immune functions rendering them dysfunctional and unable to effectively control the infection. However, in a mouse model, the therapeutic ablation of these immunosuppressive factors during persistent virus infection can restore effective anti-viral immune functions, which are then capable of dramatically accelerating virus clearance. The immune response during a persistent infection is not permanently altered and beyond repair, however the manipulation of the immune response by eliminating immunosuppressive controls can be dangerous. Therefore, it is essential to understand the mechanisms and sources of immunosuppression in order to effectively target the appropriate pathways and mediators. Ideal therapeutic strategies will simultaneously control pathogen while preventing immunopathology. Somewhere on the spectrum of immune activity, ranging from severe immunopathology to immune dysfunction and lack of pathogen control, there is a balance point where pathogen is controlled and cleared without risking the health of the host. This balance point will only be achieved through the understanding and manipulation of host derived immunosuppressive mechanisms.

Using the lymphocytic choriomeningitis virus (LCMV) model of persistent infection and subsequent immunosuppression in mice, we identified and characterized a unique dendritic cell population that expresses potent immunosuppressive mediators. Through our work we discovered that the development of suppressive dendritic cells requires the activity of type I and type II interferon, factors normally associated with immunostimulatory activity. The initial response against the virus produces a surge of type II interferon which acts on monocytes, an undifferentiated and very plastic innate immune cell, to drive their differentiation toward monocyte derived dendritic cells with the capacity for immunosuppressive functions. Subsequently, the perpetually elevated level of type I interferon signaling, due to sustained virus replication, acts on these monocyte derived dendritic cells to induce the expression of powerful immunosuppressive factors. Additionally, we found that type I interferon also restricts the expansion of another dendritic cell population capable of immunostimulatory functions. Perhaps most notably, similar suppressive dendritic cells of monocyte origin were found in other diseases associated with persistent inflammation and immunosuppression, namely Mycobacterium tuberculosis, HIV, and cancer, demonstrating the universality of our findings.

Our studies also identified the mechanism responsible for the severe disruption of thymic function during persistent LCMV. Persistent virus infection not only induced the temporal loss of thymic function, but also prevented the generation of new antiviral T cells once thymic function resumed.

Together this work has identified previously unrecognized immunological phenomena that will be informative in the development of novel therapeutic strategies aimed at restoring defective immune responses capable of eradicating persistent infections and cancer.