| Project Detail |
Background: Interferons (IFN) type I are essential in anti-viral and anti-tumor immunity. Notably, they link innate with the adaptive immunity. Chronic immune activation of the type I IFN pathway, however, promotes immune exhaustion/suppression resulting among others in the inability to control infections. Likewise, HIV-associated IFN activation strongly contributes to persistent immune activation in the chronic phase, which is causal for HIV’s progression. To prevent IFN mediated pathology, various feedback regulators exist. The ubiquitin specific peptidase 18 (USP18) plays a non-redundant key role in inhibiting IFN signaling by binding to the intracellular domain of the IFN receptor (IFNAR) a subunit 2. USP18 itself is an IFN-stimulated gene (ISG). Concordantly, its absence massively promotes type I IFN signaling. As its function in vivo cannot be easily compensated, it represents a highly promising target for immune modulation. In HIV infection, it remains largely unknown why and how USP18 is unable to constrain HIV-mediated IFN activation. In addition, USP18 is the specific protease removing ISG15 from target proteins. ISG15 is an IFN induced antiviral ubiquitin like modifier. We have been studying the IFN response in HIV-infected humanized mice over the last years. Briefly, we found that HIV infection results in prominent ISG induction, including USP18, in humanized mice. The mice did not react at all even to the high-affinity and high-potency IFN isoform IFN-?14. However, suppression of HIV replication transiently restored IFN responsiveness, as illustrated by a lower HIV burden in IFN-treated mice. Therefore, humanized mice mirror the events that occur in humans, an excellent model to study.The Main goal is to uncover the role of USP18 in HIV infection with the final objective to evaluate its role as a potential therapeutic target. In particular, we aim to dissect the functional activity of USP18 in HIV-mediated IFN activation. Very importantly, we will explore the molecular mechanisms of USP18 from different perspectives, i.e., conventional cell culture model systems, disease oriented settings and employing material derived from human patients.Notably, we aim to deepen the understanding of the USP18/ISG15 axis by studying gain and loss of function of USP18 first in vitro using cell lines and primary cells, and then in vivo using HIV-infected humanized mice. The in vivo studies will complement the in vitro approaches and permit positioning the in vitro data in a physiological context. As IFN results in intricate changes in the microenvironment we need to explore the impact of USP18 on IFN and linked to that on HIV infection at the cellular level, in vitro, as well as in a bigger context of the immune system, in vivo. Relevance: The IFN system has a key role in HIV pathogenesis. A detailed knowledge of USP18’s multifaceted function (most likely some yet to discovered) would substantially contribute to the understanding of IFNs’ role in HIV pathogenesis. The experiments outlined would also pinpoint to USP18’s role in the IFN desensitization to repetitive IFN applications. As USP18 represents a previously unaddressed target, avenues for new combinational therapies can be opened for chronic HIV infection and perhaps also for attacking the latent reservoir. |
