Completed Infection & Immunity Genetics & Molecular Biology

Viral silencing and immune evasion pathways

Funder Wellcome Charity-funded
Recipient organisation University of Cambridge
Funding £3.7M
Period Aug 2018 — Aug 2023

In plain English

AI plain-English summary

Every time a retrovirus like HIV inserts its DNA into a human cell, the cell’s defence systems try to shut that foreign DNA down—but the virus fights back, and researchers have now identified the key molecular machine on the human side of that battle. This matters because we know remarkably little about how viruses evade the cell’s natural silencing mechanisms. The team recently discovered the “Human Silencing Hub” (HUSH), a protein complex that represses newly integrated viral DNA by altering its chromatin structure. The gap is this: we do not understand how HUSH works, how lentiviruses such as HIV disable it, or how unrelated viruses that do not integrate their DNA also escape silencing. Answering these questions could reveal fundamental rules of how cells regulate their own genome. If successful, this is primarily fundamental science. It will explain how repressive heterochromatin is built and maintained, and how viruses manipulate that environment. Past fundamental work on chromatin regulation has underpinned breakthroughs in cancer epigenetics and gene therapy. In the longer term, understanding these viral countermeasures could guide the design of therapeutic tools—for example, forcing latent HIV out of hiding or blocking viral immune evasion—but no immediate clinical application is promised here.

View original technical description
Studying how viruses manipulate their host cell machinery provides insight into both viral function and cellular regulation. Invasion by viral DNA threatens cellular integrity and therefore needs to be detected and suppressed. As the default cellular response is to silence incoming DNA, how do viruses subvert and exploit this hostile environment to their advantage? Our identification of the ‘Human Silencing Hub’ (HUSH) as a novel epigenetic transcriptional repressor complex, responsible for silencing newly integrated retroviruses, has motivated us to further investigate chromatin regulation of viral infection. We wish to: (i) Understand how HUSH silences newly integrated viral DNA. (ii) Determine how lentiviruses antagonize chromatin-mediated repression and identify shared mechanisms by which unrelated, non-integrated viruses counteract silencing. (iii) Understand how and why the lentiviral-Vif accessory protein manipulates the host cell phosphoproteome. To help address these questions we have developed and optimised powerful genetic and proteomic screening technologies. Repurposing CRISPR-Cas9 will enable RNA-guided genome manipulations, including selection of informative point mutants and isolation of DNA sequence-specific regulatory proteins. Together these approaches provide a discovery platform to determine how repressive heterochromatin is established and maintained, how viruses manipulate their chromatin environment and ultimately to develop new therapeutic tools to enable their eradication.

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Researchers

Paul Lehner (EPMC Awardee)

Related Research

Grants with similar aims, by meaning.

HUSH-mediated epigenetic regulation of retroelements
Virus manipulation of host non-coding RNA regulatory networks
Viral and endogenous regulation of cellular immunoreceptors.
HIV-1 mediated reprogramming of T cell gene expression networks
Elucidating the role of host cell ncRNAs in viral replication

Original classification

Principal Research Fellowship Renewal

Plain English summaries and category classifications on this site are generated by AI and may not perfectly reflect the original research.