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| Item Type: | Preprint |
|---|---|
| Title: | Type I interferons sensitise HIV-1-reactivating T-cells for NK cell-mediated elimination despite HDACi-imposed dysregulation of innate immunity |
| Creators Name: | Prigann, J., Postmus, D., Pietrobon, A.J., Wyler, E., Jansen, J., Möller, L., Fadejeva, J., Steijaert, T., Fischer, C., Koppe, U., Gunsenheimer-Bartmeyer, B., Meixenberger, K., Vitcetz, S.N., Sohn, M., Loyal, L., Thiel, A., Sauer, S., Sutter, K., Dittmer, U., Laue, M., Bannert, N., Landthaler, M. and Goffinet, C. |
| Abstract: | Shock-and-kill is one of the most advanced, yet unrealized, concepts towards establishment of HIV-1 cure. Treatment with latency-reversing agents (LRAs), including histone deacetylase inhibitors (HDACis) exerting chromatin remodelling and gene expression reprogramming, combined with anti-retroviral therapy reactivates HIV-1 transcription in vitro, ex vivo and in vivo. However, HDACi treatment fails to significantly reduce the size of the viral reservoir in people living with HIV-1 (PLHIV). Here, by combining scRNA-seq and functional approaches, we characterised the HDACi treatment-imposed remodulation of CD4+ T-cells’ state and its consequences for HIV-1 latency reversal and the apparent resistance of HIV-1-reactivating cells to immune-mediated elimination. Exposure of CD4+ T-cells from three aviremic PLHIV with clinically applicable concentrations of Panobinostat markedly reduced the expression of genes mediating T-cell activation and IFN-driven antiviral immunity in a largely CD4+ T-cell subset-nonspecific manner, with exception of an PLHIV-specific exhausted CD4+ T-cell subpopulation. Altered transcriptomic profiles were accompanied by large refractoriness to peptide and IL-2/PHA stimulation, and to exogenous type I interferon, that would otherwise induce T-cell activation and expression of a plethora of antiviral genes, respectively. Type I interferon, when added to Panobinostat during HIV-1 reactivation, was unable to counteract HDACi-mediated inhibition of IFN signalling and failed to interfere with HIV-1 reactivation per se. However, it imposed a pre-budding block and boosted surface levels of HIV-1 Env on reactivating cells. Co-treatment with type I IFNs, most prominently IFN-β and -α14, sensitised HIV-1-reactivating cells for killing by NK cells through antibody-dependent cytotoxicity. Together, our study provides proof-of-concept of the benefit of combining a potent LRA with immunostimulatory molecules, such as type I IFNs, to reduce the resistance of HIV-1-reactivating T-cells to immune-mediated elimination to improve current shock-and-kill strategies. |
| Keywords: | HIV-1 Cure, Shock-And-Kill, Single Cell RNA-Sequencing, HDACi, Type I Interferon |
| Source: | bioRxiv |
| Publisher: | Cold Spring Harbor Laboratory Press |
| Article Number: | 2020.05.04.075119v3 |
| Date: | 19 November 2023 |
| Official Publication: | https://doi.org/10.1101/2020.05.04.075119 |
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