Antiviral Activity of Guanylate-Binding Proteins and Viral Countermeasures

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Guanylate-binding proteins (GBPs) are interferon-inducible GTPases known to play key roles in protective innate immunity against bacteria and protozoa. Humans encode seven GBP paralogs. Using evolutionary genomics and protein interaction data, we found that one of them (GBP5) shares characteristics of known antiretroviral restriction factors. Functional analyses confirmed that GBP5 restricts HIV-1 and other retroviruses by interfering with processing and virion incorporation of the viral envelope (Env) glycoprotein. The inhibitory activity of GBP5 requires isoprenylation-dependent Golgi-localization but not its GTPase function. GBP5 efficiently restricts HIV-1 in human macrophages, and some brain-derived HIV-1 strains evade this antiviral effect by an unusual tradeoff mechanism: mutations in the vpu initiation codon increase Env expression at the cost of Vpu function. Our ongoing studies demonstrate that GBP5 is also inducible by L-27 and TCR-CD3 signaling, that GBP2 also restricts lentiviral replication, and that the antiviral activity of GBP2 and GBP5 is evolutionarily conserved. In the proposed project, we want to define the exact mechanism(s) underlying restriction as well as lentiviral evasion or counteraction. Initially, we will map the amino acid residues that are critical for the antiviral activity of GBP5 and analyze their effect on Env processing, trafficking and virion incorporation. Furthermore, we will determine how the susceptibility of HIV-1 and HIV-2 to GBP2/5 inhibition evolved after transmission of SIVs from great apes and sooty mangabeys to elucidate whether GBPs constitute a barrier to successful zoonotic viral transmission. These studies will also reveal how these viruses evade or counteract the inhibitory effect of GBP2/5. Another focus will be the targeted induction of GBP2/5 expression in in primary viral target cells by different cytokines. Finally, our preliminary results show that GBP2 and GBP5 do not only inhibit retroviruses. Thus, we will analyse the effects of GBP proteins on a variety of viral pathogens, such as Influenza, Ebola, Marburg, Lyssa, Respiratory Syncytial and SARS Coronavirus. The results will yield important insights into antiviral defence mechanisms and viral countermeasures.