Key aims and expertise
Current and emerging viruses pose a significant health and economic burden worldwide. Viruses have been responsible for major pandemics and often have their origins in wildlife species (e.g. HIV/AIDS and influenza). Furthermore, viral diseases of livestock threaten food security. Hence, virologists within the University of Nottingham take a collaborative ‘one-health’ approach to research.
Research by medical virologists in the School of Molecular Medical Sciences (SMMS) focuses on hepatitis C virus (HCV) and the human immunodeficiency virus type 1 (HIV-1). The work of the medical virologists is divided into the following themes:
1. Blood-borne virus glycoprotein research
2. Clinical virology research
3. Three-dimensional tissue modelling
From livestock and companion animals to Egyptian spiny mice and elephants, virus research by Animal Infection and Immunity theme members in the School of Veterinary Medicine and Science (SVMS) encompasses the following:
1. Influenza in avian and mammalian species
2. Herpesvirus pathogenesis and control
3. Endogenous retroviruses
4. Emerging and exotic viruses
Within the School of Biosciences, the focus is on enteric viral diseases of pigs. Our focus is on porcine rotavirus, which is a leading cause of neonatal and weaning enteric disease, causing losses in production worldwide. Here our focus is:
- To better understand the mechanism by which the virus counters the host interferon response.
- To monitor circulating strains of rotavirus as part of a strategy to produce a viral vaccine to halt transmission of the virus.
- Influenza in avian and mammalian species Influenza viruses infect a wide variety of host species, including mammals such as humans, pigs and horses and birds such as chickens and ducks. The severity of disease following infection, however, can be very different, depending in part on the strain of virus but also on the host species. At SVMS we are interested in working out why some hosts are resistant to disease while others succumb to severe disease. Our work to date suggests that the cellular response in resistant hosts results in containment of virus replication and control of the inflammatory response. In contrast, in susceptible hosts, the cell response fails to control virus replication and a vigorous inflammatory response develops. Several projects involving a number of researchers are on-going to investigate the molecular basis that underlies these differences using a variety of approaches.
- Herpesvirus pathogenesis and control Herpesviruses are extremely successful colonisers, with most animal species harbouring at least one herpesvirus. By establishing latency, these viruses avoid elimination by the immune system. Within the SVMS we are working on:
Malignant catarrhal fever (MCF) – caused by the gammaherpesviruses alcelaphine herpesvirus -1 (AlHV-1) and ovine herpesvirus-2 (OvHV-2) that do not cause disease in carrier, reservoir animals (wildebeest and sheep, respectively). However, upon transmission to cattle, deer, bison and pigs MCF, a lymphoproliferative disease, occurs and is usually fatal. The pathogenesis is unique and under study using gene knockout viruses and new generation sequencing technologies. We have also developed a potential vaccine for AlHV-1 MCF that is currently undergoing field trials in Tanzania. The MCF programme is collaborative with groups from Edinburgh (MRI), Liege, Glasgow, Liverpool and Tanzania.
Equine herpesvirus-1 – can cause respiratory disease in young horses, but also late gestation abortion and neurological disease. The current focus of our research is on establishing a system to study why endothelial cells in the brain or in the placenta and uterus of pregnant mares appear to be specifically susceptible to EHV-1.
Endotheliotropic elephant herpesvirus 1 (EEHV-1) – can cause fatal disease in young captive Asian elephants. We are interested in studying how this virus is transmitted and how it causes disease in infected individuals.
- Endogenous retroviruses Retroviruses cause disease in a wide variety of species. Some of the more well-known examples include the human immunodeficiency virus (HIV) in people and the feline immunodeficiency virus (FIV) and feline leukaemia virus (FeLV) in cats. As part of their life cycle these viruses insert their genome into the host cell’s genome; if these are inserted into germ line cells (sperm or ova) they become inherited. These inherited viruses make up more of the host’s genome than the protein coding sequences in most mammalian species and have been found in every vertebrate examined to date. Work at SVMS on endogenous retroviruses is currently focussed around identifying the retroviruses present in species with genome sequence available and exploring how these viruses behave in different hosts by analysis of their expression using transcriptomics.
- Emerging and exotic viruses Viral diseases continue to emerge in new populations, animal hosts or humans on a regular basis and many involve insect transmission; the latest of these, which affects livestock in the UK and Europe, is Schmallenberg virus. Other better-known viruses seem increasingly to be emerging in new geographic areas (e.g. West Nile virus) or different species (e.g. canine influenza). Non-domestic species such as wild rodents can act as reservoirs for diseases such as hantaviruses that are able to “jump hosts” and spread to humans and domestic species. In addition, viral diseases may pose a threat to endangered animals in captivity and threaten conservation attempts. At SVMS, we are interested in the evolutionary biology, vector biology and diagnosis of emerging viruses.
- Blood-borne virus glycoprotein research Viruses such as HIV and HCV rely on interactions between their surface glycoproteins and cell receptors to gain entry into a cell. The SMMS virology group directs an international translational hepatitis C virus (HCV) research programme, the main focus of which is to gain a better understanding of this process. In particular, we are interested in defining functional and antigenic determinants and in using this knowledge to inform the development of peptide, antibody and small molecule entry inhibitors and vaccine candidates. Major achievements include: (1) the identification and characterisation, of potent and broadly neutralising murine and human monoclonal antibodies; (2) identification of glycoprotein domains and residues critical for receptor binding, entry and infectivity; (3) the discovery that selective transmission of CCR5-tropic HIV cannot be explained by selective expression of CCR5 in the female and male genital tract, and (4) that the genital tract harbours HIV strains that exhibit unusual phenotypic properties not represented by strains circulating in the periphery.
- Clinical virology research The Trent hepatitis C cohort provides a unique opportunity to study the natural history of disease progression, including correlation of fibrosis markers with histology (over 1500 liver biopsies with serum stored) and as predictors of development of cirrhosis and long term clinical complications of liver disease. Research using this unique dataset has already resulted in a number of key findings that include (1) the discovery that polymorphisms in the apoE gene and differential MBL levels are associated with HCV disease severity; (2) quantification of transition rates of liver disease progression in untreated patients defined by liver histology; (3) application of those rates in mathematical models to predict future disease burdens (de Angelis, Cambridge); (4) description and quantification of the biphasic standardised mortality rates arising from injecting drug use and liver disease within the HCV-infected population; (5) delineation of the natural history of HCV-induced severe fibrosis; and, (6) analysis of the failure of newly-diagnosed patients to enter appropriate care pathways. In addition, the Trent hepatitis C study cohort is currently undergoing meticulous genotyping and phenotyping studies with the aim of providing a unique resource for the further understanding of the pathogenesis and natural history of HCV infection and identification of new therapeutic interventions.
- Disease modelling Virologists in SMMS are working with the Department of Tissue Engineering in the University of Nottingham to develop novel three dimensional models of human liver for the study of viral pathogenesis. These models support the maintenance of hepatocyte specific functions and permit the interrogation of inflammatory signalling between parenchymal and non-parenchymal liver cells. Models are being used to study the molecular pathogenesis of HCV infection and to develop nanotechnology-based systems for the delivery of antiviral therapy.
- Major achievements of the international translational hepatitis C virus (HCV) research programme include: (i) identification and characterisation of potent and broadly neutralising murine and human monoclonal antibodies; these antibodies and their epitopes are the subject of several patents, (ii) identification of glycoprotein domains and residues critical for receptor binding, entry and infectivity, and (iii) the generation of new methods and the construction of tools for HCV glycoprotein research.
- Work on HIV pathogenesis and prevention has led to (i) the discovery that selective transmission of CCR5-tropic HIV is not due to selective expression of CCR5 in the female and male genital tract, and (ii) that different anatomical sites (e.g. brain and semen) harbour HIV strains that exhibit unusual phenotypic properties not represented by strains circulating in the periphery.