Inhibition of Infectious HIV-1 Production by Rerouting the Cellular Furin Inhibitor Serpin B8
Petersen M. Lotke R. Hopfensperger K. Victoria S. Haußmann I. Burster T. Baldauf H.-M. Sauter D.
June 2023American Society for Microbiology
Journal of Virology
2023#97Issue 6
Serpins are a superfamily of proteins that regulate a variety of physiological processes by irreversibly inhibiting the enzymatic activity of different serine proteases. For example, Serpin Family B Member 8 (Serpin B8, also known as PI8 and CAP2) binds to and inhibits the proprotein convertase furin. Like many other viral pathogens, human immunodeficiency virus type 1 (HIV-1) exploits furin for the proteolytic activation of its envelope glycoprotein (Env). Since the furin inhibitor Serpin B8 is expressed in primary target cells of HIV-1 and induced under inflammatory conditions, we hypothesized that it might interfere with HIV-1 Env maturation and decrease infectivity of newly produced virions. Indeed, recombinant Serpin B8 reduced furin-mediated cleavage of an HIV-1 Env reporter substrate in vitro. However, Serpin B8 did not affect Env maturation or reduce HIV-1 particle infectivity when expressed in HIV-1-producing cells. Immunofluorescence imaging, dimerization assays and in silico sequence analyses revealed that Serpin B8 failed to inhibit intracellular furin since both proteins localized to different subcellular compartments. We therefore aimed at rendering Serpin B8 active against HIV-1 by relocalizing it to furin-containing secretory compartments. Indeed, the addition of a heterologous signal peptide conferred potent anti-HIV-1 activity to Serpin B8 and significantly decreased infectivity of newly produced viral particles. Thus, our findings demonstrate that subcellular relocalization of a cellular protease inhibitor can result in efficient inhibition of infectious HIV-1 production. Copyright
Env , Furin , human immunodeficiency virus , Serpin B8
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Institute for Medical Virology, Epidemiology of Viral Diseases, University Hospital Tübingen, Tübingen, Germany
School of Sciences and Humanities, Nazarbayev University, Astana, Kazakhstan
Max von Pettenkofer Institute and Gene Center, Virology, National Reference Center for Retroviruses, Faculty of Medicine, LMU Munich, Munich, Germany
Institute for Medical Virology
School of Sciences and Humanities
Max von Pettenkofer Institute and Gene Center
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