Team Human Innate Immunity
Innate immune responses are considered the first defensive line against harmful conditions, including cancer. Human dendritic cells play a key role in the control of these responses and are a promising constituent of rational immune therapies. Indeed, dendritic cells possess a unique machinery to detect and sense injured tissues, cellular fragments and pathogens. Upon detection, dendritic cells become licensed to activate adaptive immunity and thus couple innate and adaptive responses. We use HIV, an important human pathogen that causes AIDS, as a model to understand the regulation of innate immunity in human dendritic cells (Figure 1).
We have discovered that an innate immune response to HIV-1 exists in dendritic cells. HIV-1 is normally unable to infect dendritic cells and we have used the Vpx protein found in other lentiviruses to render dendritic cells susceptible to HIV-1 infection. In these conditions, infection of dendritic cells results in induction of an innate immune response that can prime adaptive immunity and induce protective antiviral type I interferon. HIV-2, which is less pathogenic than HIV-1, encodes Vpx and naturally infects and induces an innate immune response in dendritic cells, pointing to an important role of this response in determining the ability of the immune system to control HIV replication.
We recently showed that innate immune sensing of HIV by dendritic cells is mediated by the cytosolic DNA sensor cGAS. In the virus, the viral DNA is required for cGAS activation. The viral DNA is embedded in a shell of viral capsid proteins, and we showed that the viral capsid determine the fate of the viral DNA towards viral replication or innate immune recognition. In addition, we showed that the binding of host protein Cyclophilin A to capsid is a key regulator of HIV sensing by dendritic cells.
Based on these findings, we now explore new avenues of research. Our first aim is to identify novel regulators of the innate immune response and the viral replication. Our second aim is to characterize the type of adaptive immune response that will be generated in T cells when the innate immune response to HIV-1 is active in dendritic cells. Lastly, we explore more general aspects of innate immune regulation. In particular, we focus on the regulation and functions of the important sensor cGAS in immune cells. To achieve these aims, we utilize a number of molecular and cellular approaches, including RNAi in dendritic cells, functional screens and analysis of gene networks. Our results suggest new ways to generate adjuvants for immunotherapies and vaccines. A patent application has been filed accordingly.