Plasmacytoid dendritic cells contribute to HIV diseases and viral persistence via IDO-dependent mechanisms

Abstract

Abstract The combination antiretroviral therapy (cART) effectively suppresses HIV replication and enables HIV-infected individuals to live long-productive lives. However, the persistence of HIV reservoir cells with latent or lowreplicating HIV in patients under cART make HIV infection an incurable disease. Plasmacytoid dendritic cells (pDCs) suppress HIV replication through secreting type I interferon (IFN-I). We have reported that pDCs play a major pathogenic role in chronic HIV infection in vivo. In this study, we discovered that pDCs-depletion during cART completely resolved HIV immune pathogenesis and rescued anti-HIV T cell response in humanized mice. Importantly, HIV reservoirs (total cell-associated HIV DNA as well as cells with replication-competent HIV virus) are reduced by pDCs-depletion. We showed that HIV infection induced IDO expression in monocytes and DC via pDC-dependent mechanism. Interestingly, IDO inhibition during cART similarly resolved HIV immune pathogenesis and rescued anti-HIV T cell response, correlated with reduced HIV reservoirs in humanized mice in vivo. Finally, we proved that pDCs depletion and IDO inhibition acted through the same pathway to reverse HIV pathogenesis. We conclude that pDCs persistently activated by HIV lead to IDO expression that induces host immune exhaustion, contributing to HIV reservoirs persistence during effective cART. Strategies to disrupt the pDC-IDO axis will provide novel opportunities to achieve HIV-1 functional cure therapy.