Natural Cystatin C fragments inhibit GPR15-mediated HIV and SIV infection without interfering with GPR15L signaling

Hayn, M.; Bloetz, A.; Rodriguez-Alfonso, A.; Vidal, S.; Preising, N.; Staendker, L.; Wiese, S.; Stuerzel, C. M.; Harms, M.; Gross, R.; Jung, C.; Kiene, M.; Hahn, B. H.; Jacob, T.; Poehlmann, S.; Forssmann, W.-G.; Muench, J.; Sparrer, K. M.; Seuwen, K.; Kirchhoff, F.

doi:10.1101/2020.10.26.355172

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bioRxiv · 10.1101/2020.10.26.355172

Natural Cystatin C fragments inhibit GPR15-mediated HIV and SIV infection without interfering with GPR15L signaling

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Abstract

GPR15 is a G protein-coupled receptor proposed to play a role in mucosal immunity that also serves as entry cofactor for HIV and SIV. To discover novel endogenous GPR15 ligands, we screened a hemofiltrate-derived peptide library for inhibitors of GPR15-mediated SIV infection. Our approach identified a C-terminal fragment of Cystatin C (CysC95-146) that specifically inhibits GPR15-dependent HIV-1, HIV-2 and SIV infection. In contrast, GPR15L, the chemokine ligand of GPR15, failed to inhibit virus infection. We found that Cystatin C fragments preventing GPR15-mediated viral entry do not interfere with GPR15L signaling and are generated by proteases activated at sites of inflammation. The antiretroviral activity of CysC95-146 was confirmed in primary CD4+ T cells and is conserved in simian hosts of SIV infection. Thus, we identified a potent endogenous inhibitor of GPR15-mediated HIV and SIV infection that does not interfere with the physiological function of this G protein-coupled receptor.

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Hayn, M., Bloetz, A., Rodriguez-Alfonso, A., Vidal, S., Preising, N., Staendker, L., Wiese, S., Stuerzel, C. M., Harms, M., Gross, R., Jung, C., Kiene, M., Hahn, B. H., Jacob, T., Poehlmann, S., Forssmann, W.-G., Muench, J., Sparrer, K. M., Seuwen, K., Kirchhoff, F.. 2020-10-26. Natural Cystatin C fragments inhibit GPR15-mediated HIV and SIV infection without interfering with GPR15L signaling. https://doi.org/10.1101/2020.10.26.355172

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