Community Research and Development Information Service - CORDIS

ERC

Anti-Virome Report Summary

Project ID: 323035
Funded under: FP7-IDEAS-ERC
Country: Germany

Final Report Summary - ANTI-VIROME (A combined evolutionary and proteomics approach to the discovery, induction and application of antiviral immunity factors)

Antiviral restriction factors play a key role as a first line of defense against invading viruses. They target almost every step of the viral replication cycle and show a striking structural and functional diversity. Nonetheless, restriction factors also have some characteristic features, such as antiviral effects, interferon-inducibility, high genetic variability and species specificity. This project aims to use combined proteomics and evolutionary approaches to discover and characterize as-yet-unknown antiviral effectors and their inducers. Collaborative genome-wide screens showed that a very limited number of human genes share the molecular and evolutionary characteristics of known antiretroviral restriction factors, such as TRIM5α, APOBEC3G, Tetherin and SAMHD1. Functional analyses of the most promising candidate restriction factors for their antiretroviral activity showed that IFNγ-inducible protein 16 (IFI16) and guanylate binding protein 5 (GBP5) efficiently inhibit the production of infectious HIV-1 and other primate lentiviruses. IFI16 affects viral gene expression and the activity of the HIV promoter, whereas GBP5 affects viral infectivity by interfering with the processing and virion incorporation of the envelope glycoprotein. Interestingly, both of these IFN-inducible factors don’t inhibit retroviruses directly but affect the availability of essential virus dependency factors, i.e. the cellular protease furin that is critical for the maturation and function of viral Envelope glycoproteins and the transcription factor Sp1, which is critical for effective viral gene expression. Notably, IFI16 and GBP5 are both active against a broad variety of viral pathogens. Another goal of this project is to examine the co-evolution of primate lentiviruses and their hosts to clarify which adaptations allow HIV-1 to spread efficiently in the human population. Initially, we showed that effective Vape-mediated tetherin antagonism might explain why the M group of HIV-1 is almost entirely responsible for the AIDS pandemic. More recently, we showed that the Nef proteins of epidemic HIV-1 group O strains antagonize human tetherin, which was highly surprising because all previous studies suggested that a deletion in human tetherin generally confers Nef resistance. Notably, our ongoing studies demonstrated that the restriction factor tetherin already emerged at least 450 million years ago. Furthermore, we found that Vpu targets antiviral factors not only directly but also suppresses their transcription by inhibiting the activity of the transcription factor NF-κB. We provide evidence that human-specific adaptations in the HIV-1 Vpu protein that confer potent anti-tetherin activity are indeed critical for IFN resistance and viral replication in vivo. In addition, we showed that HIV-1-characteristic properties contribute to the high levels of chronic inflammation that drive AIDS progression in humans but are unable to overcome protective host mechanisms in well-adapted monkey species. Finally, we screened complex peptide-protein libraries representing essentially the entire human peptidome for novel specific inducers of antiviral restriction factors. We discovered a highly specific endogenous antagonist of CXCR4 and showed that optimized derivatives thereof show beneficial effects against cancers and inflammatory diseases in mouse models. The clinical perspectives of the CXCR4 antagonist are now further examined in a Proof of Concept grant. Altogether, we feel that significant progress has been made in the present project to achieve a better understanding of the network of inducers and effectors of antiviral immunity. Furthermore, optimized derivatives of the endogenous CXCR4 inhibitors may allow treating cancers and inflammatory disorders and thus having relevance beyond HIV/AIDS.

Reported by

UNIVERSITAET ULM
Germany
Follow us on: RSS Facebook Twitter YouTube Managed by the EU Publications Office Top