REGULATION OF INNATE VIRAL SENSING AND CHRONIC INFLAMMATION
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Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) are chronic viral infections that affect hundreds of millions of individuals worldwide. Despite significant advancements in treatment, increasing evidence suggests that chronic inflammatory medical illnesses occur more frequently and at earlier ages in HIV and HCV infected individuals. Defining the causes of chronic inflammation is key to understanding the pathogenesis of these infections and to developing novel therapeutic treatments of chronic disease. Innate sensing of viral infections is key to early control of infection and occurs through multiple pathways. Inflammasomes are large multiprotein complexes that play a central role in inflammation associated with viral infection. Inflammasome assembly and activation of caspase-1 results in the cleavage of the pro-forms of IL-1β and IL-18 into active, mature cytokines that are known to mediate inflammation. Elevated IL-18 has been identified in a number of inflammatory conditions. We have shown that IL-18 is significantly elevated in HIV/HCV coinfection compared to HIV or HCV monoinfection. This elevation is most likely due to innate sensing of both viruses, correlates directly with detectable HIV viral load and inversely with CD4 counts. Given the association with increased IL-18 and inflammatory conditions seen with these infections, this finding may explain the enhanced disease progression observed in coinfected individuals. Type I interferons (IFN) play a dichotomous role in chronic viral infections. These inflammatory cytokines are essential in controlling acute infection and slowing disease progression, yet contribute to chronic immune activation and pathogenesis of disease. We have shown a novel regulation mechanism for IFN produced by pDCs in response to HIV. HIV specific antibodies can both suppress and enhance the IFN response by pDCs and may explain the persistent IFN response seen in HIV infection that has been linked to immune activation and pathogenesis. Inflammatory responses are critical for host response to pathogens and the development of the adaptive immune response while being associated with pathogenesis. Therefore, a greater understanding of the balance between beneficial and detrimental inflammatory responses is needed. Not all inflammation can be considered harmful, therefore therapeutic inhibition of these pathways must be balanced against their beneficial contributions.