Abstract
BackgroundHIV-1 protease (PR) is essential for viral infectivity as it cleaves Gag and Gag-Pol polyprotein precursors during viral maturation. Recent evidence suggests that cellular proteins can also be cleaved by PR, perhaps representing an important viral strategy to counter host defense mechanisms. Receptor-interacting protein kinase 1 (RIPK1) and RIPK2 belong to a family of serine/threonine kinases with conserved domain architecture and important functions in apoptosis, necrosis and innate immunity.ResultsWe found that RIPK1 and RIPK2 but not other members of the RIP kinase family are cleaved by HIV-1 PR. In RIPK1, we identified a putative PR cleavage site; a mutation at this site rendered RIPK1 resistant to PR cleavage. RIPK1 and RIPK2 were cleaved during HIV-1 infection of T cell lines or primary activated CD4+ T cells. Interfering with the viral life cycle at different stages by the addition of specific inhibitors against RT, integrase, or PR, completely prevented RIPK1 and RIPK2 cleavage. Cleavage of RIPK1 disrupted RIPK1/RIPK3 complex formation and RIPK1-mediated induction of NF-kB.ConclusionsThese findings indicate that RIPK1 and RIPK2 are targets of HIV-1 PR activity during infection, and their inactivation may contribute to modulation of cell death and host defense pathways by HIV-1.Electronic supplementary materialThe online version of this article (doi:10.1186/s12977-015-0200-6) contains supplementary material, which is available to authorized users.
Highlights
human immunodeficiency virus type 1 (HIV-1) protease (PR) is essential for viral infectivity as it cleaves groupspecific antigen (Gag) and Gag-Pol polyprotein precursors during viral maturation
We found that PR can interact with Receptor-interacting protein kinase 1 (RIPK1), but not RIPK3
We have found that RIPK1 and RIPK2 are novel host substrates of HIV-1 PR
Summary
HIV-1 protease (PR) is essential for viral infectivity as it cleaves Gag and Gag-Pol polyprotein precursors during viral maturation. Recent evidence suggests that cellular proteins can be cleaved by PR, perhaps representing an important viral strategy to counter host defense mechanisms. Many aspects of the viral life-cycle, including entry, integration and release of viral particles, rely on a complex network of interactions between viral and host proteins. Cells targeted by HIV-1 express a number of proteins that function to restrict HIV-1 infection, including TRIM5α [2, 3], APOBEC3G [4,5,6,7] and Tetherin [8, 9]. The main function of the HIV-1 protease (PR) is to cleave the viral polypeptides Gag and Gag-Pol into mature proteins.
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