RJ GIFFORD

Virology | Evolution | Genomics

New frontiers in virus research

Rob Gifford.

Genome sequencing technologies have revolutionised virology. My research aims to take advantage of these transformative advances to explore fundamental aspects of virus biology and evolution.

My research is primarily computational, but I also work closely with doctors, veterinarians, epidemiologists and wet lab-based molecular biologists. My research cover several related themes, outlined below.

1. Applied virus genomics

1.1. Treatment of hepatitis C virus infection

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease, and infects >70 million people worldwide. Antiviral drugs can cure HCV infection but efficacy of treatment varies according to factors associated with genetic variation. Analysis of genomic data can help optimise treatment of HCV-infected individuals, and guide the development of strategies for eliminating HCV infection entirely.

To support this, we have developed HCV-GLUE - a sequence-based resource for HCV that links a large set of richly-annotated, highly organised virus genome sequences with information about drug efficacy.

We are collaborating with CVR investigators John McLauchlan and Emma Thomson, along with two national HCV research initiatives (STOP HCV and HCV Research UK), to further develop this resource as a tool supporting clinical decision-making in HCV treatment programmes.


1.2. Surveillance & monitoring of pathogenic viruses

Genomic data can be used to survey epidemics of viral disease, and to trace virus spread between individuals, populations, and geographic regions.

We are developing resources for bluetongue virus (BTV) and rabies virus (RABV) that are designed to support genomic surveillance and outbreak response initiatives for these animal pathogens.

For bluetongue virus, we have established the first online database focussed on collating genomic data: BTV-GLUE. Currently, we are working with Massimo Palmarini to establish an overview of BTV genetic diversity, and determine the geographic associations of particular strains. Through our involvement in PALE-BLUE we plan to link BTV-GLUE with a database of BTV isolates held at Pirbright.

For rabies virus, we have established an offline database and fledgling strain-typing tool. Currently, we are working with Katie Hampson and collaborators at BACHM to further develop this resource.


1.3. Comparative genomics for experimental virology

Genomic data can inform basic, experimental investigations of virus replication. Our work in this area mainly focuses on human immunodeficiency virus type 1 (HIV-1). We are part of the Center for HIV RNA Studies (CRNA): an integrated team of biophysicists, cell and computational biologists, chemists, and virologists dedicated to understanding the role of RNA in HIV replication.

We have developed sequence-based resources to support the experimental work being performed on HIV-1 by the CRNA, and by our CVR collaborators Sam Wilson and Suzannah Rihn.



2. Coevolution of viruses and their hosts

2.1. Paleovirology

We make extensive use of endogenous viral elements (EVEs) in our research. EVEs are DNA sequences derived from ancient viruses (paleoviruses) that occur in the genomes of eukaryotic organisms. We have developed a computational approach for exploring the diversity of EVEs in published genome sequence data, called database-integrated genome screening (DIGS).

We organise EVE sequences recovered via DIGS using our software package GLUE, to expedite their further use in virological and genomic research. In our own research, we are exploiting these GLUE-based resources in a variety of ways:

Firstly, EVE sequences are similar in some ways to 'virus fossils' - they provide unique retrospective information about extinct viruses and their interactions with ancestral host species. We use comparative approaches to mine the EVE 'fossil record' for information about virus ecology and evolution.

In addition, we are investigating the biological properties of extinct viruses that gave rise to EVEs, through our collaborations with experimental virologists.

Finally, we are using EVE data to examine the impact of horizontal gene transfer from viruses on the evolution of eukaryotic genomes (see section 2.2. below)


2.2. Impact of viruses on host genomes

The immense selective pressure that viruses have exerted on host species has left a deep imprint on their genomes. One aspect of this related to antiviral defence - host species have evolved an arsenal of antiviral genes that block viral infections.

Type I interferon (IFN) is a master regulator of antiviral genes, and can trigger the expression of hundreds of IFN-stimulated genes (ISGs), many of which have antiviral activity. As part of the CVR's innate immunity research programme, we are performing comparative genomic analyses to investigate the evolution of the mammalian interferome.

Also - and in close relation to our 'paleovirological' work (section 2.1 above) - we are interested in how horizontal transfer of genetic information from virus to host genomes has impacted evolution. One of the most remarkable things to be revealed by genomics is the extent to which viruses and transposons have influenced eukaryotic genome evolution.

In particular, retroviruses have viruses have been motors of genome evolution in mammals. We are collaborating with Helen Rowe at University College London to investigate how epigenetic modulation of endogenous retroviruses has contributed to the evolution of gene regulatory networks in mammals.


2.3. Impact of technology on viral emergence

The historical role that technology has played in enabling viral emergence is a developing theme in our research.

Until fairly recently, it was only possible to speculate about what drove the emergence of contemporary viral diseases. However, as more genomic data become available (including some that preserve retrospective information) we increasingly have the means to explore these questions.

We have used genetic data to demonstrate a likely role for experimental malaria studies, and later the development of avian cell culture techniques, in facilitating the iatrogenic transmission of a retrovirus to birds. More recently, we have been reconstructing the events that enabled pandemic spread of small ruminant lentiviruses (the sheep and goat equivalents of HIV-1).



3. Software development

3.1. GLUE - a power tool for virus genomics

We have developed GLUE, a bioinformatics environment for virus sequence data that not only facilitates the implementation of diverse, data-oriented resources for viruses, but also supports the stable development of these resources as reusable digital assets.


3.2. The DIGS tool - heuristically exploring genome databases

A significant fraction of most genomes is comprised of DNA sequences that have been incompletely investigated. This genomic ‘dark matter’ contains a wealth of useful biological information that can be recovered by systematically screening genomes in silico using sequence similarity search tools. Specialized computational tools are required to implement these screens efficiently. The database-integrated genome-screening (DIGS) tool is a computational framework for performing these investigations.


Former Research Group Members

Joshua B. Singer (Postdoctoral Research Software Engineer)

Anna-Maria Niewiadomska (Postdoctoral Research Assistant)

Tristan Dennis (PhD student)

Henan Zhu (PhD student)

Daniel Blanco-Melo (PhD student)

Suzannah Rihn (PhD student)

Megan Robinson (MSc student)

Aaron Weckworth (MSc student)

Kathryn Evans (Student intern)

Alexander MacLeod (Student intern)

Soledad Marsile-Medun (Student intern)

Media

WIRED 2017 Prehistoric ancestor of leukaemia is found in 45-million-year-old bat species
Science 2014 Viruses may explain why small animals are more prone to cancer
BBC 2014 Ancient virus DNA thrives in us
National Geographic 2013 The Amazing Story of a Mammal Virus That Became a Bird One
New York Times 2011 Hunting fossil viruses in human DNA
The Guardian 2009 Research shows HIV's ancestor millions of years older than believed
New Yorker 2006 Darwin's Surprise