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Wellcome-MRC Cambridge Stem Cell Institute




Professor Paul Lehner

Chromatin Control of Viral Infection

Departmental affiliation: Cambridge Institute of Therapeutic Immunology & Infectious Diseases (CITIID)



Paul Lehner is a Wellcome Trust Principal Research Fellow. His research programme focuses on the use of genome wide CRISPR genetic approaches to identify novel genes and intracellular pathways involved in virus:host interactions with a particular emphasis on epigenetic mechanisms of viral silencing. He is also a practising Infectious Diseases Physician at Addenbrooke's Hospital in Cambridge.


All life forms defend their genome against DNA invasion. Mammalian cells counteract this threat to cellular integrity through innate immune system activation (e.g. release of interferon). Cells also silence the incoming DNA, prior to transcription. Indeed DNA silencing through chromatinisation likely represents the default pathway. Perversely, viruses not only introduce and replicate their nucleic acid, but recruit host machinery to enable replication. Persistent viral survival depends on their ability to evade immune recognition, as well recognized with interferon antagonism, but less well realized in the context of DNA silencing.

Viruses adopt different strategies to enhance, prevent or de-repress silencing and are adept at manipulating their chromatin environment. Uniquely, retroviruses reverse transcribe their RNA into dsDNA and integrate into host chromosomal DNA ie they ‘become genes’. By aligning regulation of their viral genome with the host, retroviral integration allows unintegrated, poorly expressed retroviruses to escape extrachromosomal silencing. While most integrations are transcriptionally active, for HIV, the most clinically important lentivirus, it is the silenced, integrated HIV proviral pool which defies eradication and mandates lifelong HIV treatment.

We use genetic and proteomic technologies to understand different mechanisms of DNA silencing and how viruses usurp and overcome these pathways. For example we recently discovered the HUSH epigenetic repressor complex which silences incoming lentiviruses like HIV. Remarkably HUSH also silences endogenous mobile retrotransposons like LINE-1 elements, which make up 17% of our genome. Our work provides unique insight into chromatin regulation and potential opportunities for manipulating these pathways.