NK cells lacking CD56 (CD56 ) were first identified in chronic HIV-1 infection. However, CD56 NK cells also exist in healthy individuals, albeit in significantly lower numbers. Here, we provide an extensive proteomic characterisation of human CD56 peripheral blood NK cells of healthy donors and compare them to their CD56 and CD56 counterparts. Unbiased large-scale surface receptor profiling clustered CD56 cells as part of the main NK cell compartment and indicated an overall CD56 -like phenotype. Total proteome analyses of CD56 NK cells further confirmed their similarity with CD56 NK cells, and revealed a complete cytolytic inventory with high levels of perforin and granzyme H and M. In the present study, twelve proteins discriminated CD56 NK cells from CD56 NK cells with nine up-regulated and three down-regulated proteins in the CD56 NK cell population. Those proteins were functionally related to lytic granule composition and transport, interaction with the extracellular matrix, DNA transcription or repair, and proliferation. Corroborating these results, CD56 NK cells showed modest cytotoxicity, degranulation, and IFN-ɣ secretion as compared to CD56 NK cells. In conclusion, CD56 NK cells constitute functionally competent cells sharing many features of bona fide CD56 NK cells in healthy individuals, but with some distinct characteristics.

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During viral infections, cell death can be induced as a direct result of cytopathic virus replication in various cell types and tissues or as an immune response of the host to the infectious agent. This leads to an infiltration of inflammatory cells, causing subsequent tissue damage. The balance between effective elimination of the pathogen and prevention of fatal tissue damage is decisive for life. The host has developed various mechanisms to inhibit excessive immune responses.

While a drug treatment is unavailable, the global incidence of Dengue virus (DENV) infections and its associated severe manifestations continues to rise. We report the construction of the first physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model that predicts viremia levels in relevant target organs based on preclinical data with the broad spectrum antiviral soraphen A (SorA), an inhibitor of the host cell target acetyl-CoA-carboxylase. SorA was highly effective against DENV in vitro (EC50 = 4.7 nM) and showed in vivo efficacy by inducing a significant reduction of viral load in the spleen and liver of IFNAR–/– mice infected with DENV-2. PBPK/PD predictions for SorA matched well with the experimental infection data. Transfer to a human PBPK/PD model for DENV to mimic a clinical scenario predicted a reduction in viremia by more than one log10 unit for an intravenous infusion regimen of SorA. The PBPK/PD model is applicable to any DENV drug lead and, thus, represents a valuable tool to accelerate and facilitate DENV drug discovery and development.