Characterization of the secretory glycoprotein 90K as an antiviral restriction factor

• Applicant: Professorin Dr. Christine Goffinet
• Subject Area: Virology
• Term: from 2013 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 235106124

In response to viral infections, interferons induce the transcription of several hundred genes in mammalian cells. Specific antiviral functions, however, have only been attributed to a few of them. 90K/LGALS3BP is an interferon-stimulated gene that encodes for a secretory glycoprotein. We established 90K as a potent antiviral effector that reduces the infectivity of progeny HIV-1. The cell-associated, but not the secreted species of 90K exerted the antiviral activity. 90K interfered with the proteolytical maturation of the HIV-1 envelope glycoproteins and their incorporation into newly synthesized virions, resulting in the release of poorly infectious particles. Depletion of 90K expression alleviated the antiviral impact of interferon treatment, highlighting the importance of this interferon-stimulated gene product in establishing an antiviral state. Excitingly, the accessory protein HIV-1 Vpr antagonizes the antiviral activity of 90K by an unknown mechanism. Thus, 90K constitutes a novel antiviral restriction factor that employs an unprecedented mode of action, and may thus be exploited for antiviral therapy. The overall goal of this research proposal is the in depth-characterization of the antiviral properties of the secretory glycoprotein 90K. We plan to elucidate the mechanism of 90K-imposed inhibition, to assess the contribution of 90K to the inhibition of HIV-1 in T-cells, to define the breadth of 90K-imposed restriction and its evolutionary conservation. Importantly, we will characterize the mechanism of 90K antagonism employed by HIV-1 Vpr. The expected outcome of this project is an improved understanding of how the novel anti-HIV-1 restriction factor 90K contributes to the cellular defence against viral infections. Importantly, deciphering the HIV-1 Vpr-mediated counteraction of 90K may explain the apparently poor influence of the restriction factor in vivo, and these findings might nourish future studies aiming at the design of therapeutic strategies that exploit the antiviral activity of 90K or that circumvent the viral antagonism of 90K.

• DFG Programme: Research Grants