Cellular restriction of HIV-1 by 90K and SERINC5 and their sensitivity to evasion through viral cell-to-cell spread
Immunofluorescence analysis of 90K (red) and HIV-1 Env (green)
Immune cells respond to a viral infection by synthesis of antiviral cytokines, interferons. Firstly described in the late 50s as molecules that interfere with Influenza Virus infection (thus “interferons”), they have been established as multipotent molecules, with roles within immune stimulation, anti-tumor and anti-viral defense. Type I interferons count to the most efficient defenders against viral infections. After recognition of pathogen-associated molecular patterns (PAMPs), interferons are synthesized, secreted and bind the interferon receptor on neighboring cells to „alarm“ them from an upcoming virus invasion. Binding induces a signaling cascade that ultimately results in synthesis of several interferon-stimulated genes, so-called ISGs (“interferon-stimulated genes”). ISGs comprise many antiviral genes, encoding among other APOBEC3G, a cellular deaminase which hypermutates the viral genome, or Tetherin, which prevents release of mature virions from the producer cell´s surface. Another ISG is lgals3bp, which encodes for the cellular glycoprotein 90K. Previous work of the group demonstrated the antiviral potency of 90K against HIV. Specifically, 90K reduces the infectivity of newly assembled virions by interfering with the viral incorporation of HIV Envelope proteins – these are essential for initiating a new infection. The group of Christine Goffinet is now focusing on the elucidation of the antiviral mechanism. The long-term perspective is to pave avenues towards a new antiviral treatment strategy.
Scientific work programme
The mode of action by which 90K reduces the incorporation of HIV-1 Envelope proteins remains elusive to date. Using truncated versions of 90K, we plan to define which domains/regions within 90K are essential and sufficient for its antiviral function. In parallel, 90K orthologs from non-human species, which share a high degree of homology with human 90K, but differ in their antiviral capability, are useful tools for the elucidation of the antiviral mechanism.
Further, they shed light on the evolutionary conservation of 90K´s antiviral function. In collaboration with Prof. Thomas Krey (Project B10), we aim at elucidating the structure of active and inactive 90K variants. In collaboration with Prof. Abel Viejo-Borbolla (Project B9), we aim at identifying potential inhibition of other enveloped viruses by 90K.
Christine Goffinet is talking about her research at the CRC 900
Christine Goffinet joined the CRC in the second funding period in 2014. Her project C8 focuses on the characterisation of the human 90K glycoprotein, which shows antiviral properties against HIV.
Publications of the project C8
Inactivation of HCV and HIV by microwave: a novel approach for prevention of virus transmission among people who inject drugs. Siddharta A, Pfaender S, Malassa A, Doerrbecker J, Anggakusuma, Engelmann M, Nugraha B, Steinmann J, Todt D, Vondran FW, Mateu-Gelabert P, Goffinet C, Steinmann E. Sci Rep. 2016 Nov 18;6:36619.
cGAS-Mediated Innate Immunity Spreads Intercellularly through HIV-1 Env-Induced Membrane Fusion Sites. Xu S, Ducroux A, Ponnurangam A, Vieyres G, Franz S, Müsken M, Zillinger T, Malassa A, Ewald E, Hornung V, Barchet W, Häussler S, Pietschmann T, Goffinet C. Cell Host Microbe. 2016 Oct 12;20(4):443-457.
Cellular Antiviral Factors that Target Particle Infectivity of HIV-1. Goffinet C. Curr HIV Res. 2015 Dec 16. Review.
The Antiviral Activity of the Cellular Glycoprotein LGALS3BP/90K is Species-Specific. Lodermeyer V, Ssebyatika G, Passos V, Ponnurangam A, Malassa A, Ewald E, Stürzel CM, Kirchhoff F, Rotger M, Falk CS, Telenti A, Krey T, Goffinet C. J Virol. 2018 May 9. pii: JVI.00226-18.
SIVcol Nef counteracts SERINC5 by promoting its proteasomal degradation but does not efficiently enhance HIV-1 replication in human CD4+ T cells and lymphoid tissue. Kmiec D, Akbil B, Ananth S, Hotter D, Sparrer KMJ, Stürzel CM, Trautz B, Ayouba A, Peeters M, Yao Z, Stagljar I, Passos V, Zillinger T, Goffinet C, Sauter D, Fackler OT, Kirchhoff F. PLoS Pathog. 2018 Aug 20; 14(8):e1007269.
Prof. Christine Goffinet
Charité – Universitätsmedizin Berlin, Germany
Berlin Institute of Health
Institute of Virology
BIH Professor for Virology
Charité Campus Mitte
+49 30 450 525-489