Lishan Su, PhD, Professor
Department of Microbiology & Immunology
Lineberger Comprehensive Cancer Center
UNC School of Medicine
Plasmacytoid dendritic cells (pDC) are the major type I interferon (IFN-I) producing cells and play important roles in antiviral immune responses. However, sustained pDC activation and IFN-I induction has been correlated with disease progression in chronic virus infection. We have recently defined the HIV-pDC-IFN axis in HIV-1 immuno-pathogenesis, and studied the mechanisms of pDC/IFN-induced immune suppression, and its role in HIV reservoir persistence.
During persistent HIV-1 infection, we have shown that blocking the IFN-I receptor (IFNAR) with an mAb (bAb) reversed HIV diseases in the presence of elevated HIV-1 replication in humanized mice, essentially “phenocopying” pDC depletion. In HIV-infected mice with cART, IFNAR bAb or pDC depletion induces HIV blips, associated with reversion of immune hyper-activation, functional recovery of human immune cells and reduction of HIV+ reservoirs.
We conclude that low levels of IFN-I signaling contribute to the immune dysfunction and foster HIV-1 persistence in cART-treated hosts. Our results suggest that blocking IFNAR may provide a novel strategy to enhance immune recovery and to reduce HIV-1 reservoirs during suppressive cART. Our findings thus not only functionally define the role of pDC/IFN-I in HIV-1 disease progression, the IFNAR blocking and pDC-depleting mAb will also be developed into novel therapeutics to i) enhance immune recovery in immune non-responder patients under cART and ii) achieve control of HIV rebound after cART interruption.