Control of feline immunodeficiency virus infection - resubmission
Lead Research Organisation:
University of Glasgow
Department Name: Veterinary Infection and Immunity
Abstract
Feline immunodeficiency virus (FIV) infects approximately 500 thousand domestic cats in the UK. Infected cats may develop numerous infections, tumours and display neurological signs. In our survey to find out what happened to infected cats, 53% died or were euthanased, 25% suffered recurrent episodes of illness and 22% remained healthy. To control FIV infection requires a safe, effective vaccine. However there are many obstacles to developing a vaccine, particularly because the virus continually changes its outer shell and thus hides from the immune system. Moreover, infected cats do not recover from infection; whereas influenza virus triggers an immune response that clears virus from the body, FIV infection persists. We aim to devise laboratory techniques that can determine whether an infected cat is likely to remain well for some years or whether it is more likely to become terminally ill and require euthanasia. This information will assist veterinarians and owners to manage each infected cat and will assist in the re-homing of infected animals. Our second aim is to determine why some virus isolates cause more serious disease than others. If we can identify the main characteristics of a strain of virus that are associated with disease in infected cats, we will be able to structure therapy and management more appropriately.
Technical Summary
Feline immunodeficiency virus (FIV) infects approximately 0.5 million domestic cats in the UK. Infected cats may develop numerous infections, including gingivitis/stomatitis, anorexia and wasting, neurological signs and malignancies. In a recent survey to determine the prognosis for FIV-infected cats, 53% of infections proved fatal died or resulted in euthanasia, 25% suffered recurrent episodes of illness and 22% remained healthy. To control FIV infection requires a safe and effective vaccine. However there are many obstacles to developing such a vaccine, particularly because the virus is able to mutate rapidly and thus evade both the humoral and cellular arms of the immune system. Moreover, infected animals do not recover from infection; whereas influenza virus triggers an immune response that clears virus from the body, FIV infection persists in the face of a potent immune response. The first aim of this project is to devise laboratory techniques that will enable us to determine whether an infected cat is likely to remain well for some years or whether it is more likely to become terminally ill and require euthanasia. These studies are based on our recent findings that viruses isolated during the early and late phases of infection have distinct biological phenotypes in vitro and pathogenicities in vivo. Accordingly, if we can ascertain the biological phenotype of a virus reliably, we will be able to stage more accurately the infection and design appropriate therapeutic interventions and management strategies for veterinarians and owners. Env genes will be cloned from primary isolates of virus and their biological properties assessed in vitro by generating chimaeric molecular clones; the production of HIV (FIV) viral pseudotypes to assess the receptor usage and cell tropism, and comparing the in vitro growth of chimaeric viruses with the parent strains in a panel of feline cell lines and primary cells. In the second aim, we will ask whether quasispecies diversity is linked to pathogenicity. It is thought that a heterogeneous viral population may be more difficult for the host immune response to control and may also achieve higher viral loads and wider dissemination within the host. We have examined the diversity of a single highly pathogenic strain of FIV and have found it to contain a range of viable viral variants. We will investigate the diversity of env genes isolated from isolates of low and high virulence by direct amplification using PCR. We will compare the in vivo properties of viruses with a heterogeneous population of env genes with that of a single env species. If we can identify the main characteristics of a strain of virus that are associated with disease in infected cats, we will be able to structure therapy and management more appropriately. We will monitor infection to assess whether a single viral genotype dominates with time post-infection using high-throughput capillary sequencing and heteroduplex tracking assay (HTA).
Publications
Willett BJ
(2013)
Feline leukaemia virus: half a century since its discovery.
in Veterinary journal (London, England : 1997)
Willett BJ
(2009)
Enforced covalent trimerisation of soluble feline CD134 (OX40)-ligand generates a functional antagonist of feline immunodeficiency virus.
in Molecular immunology
Willett BJ
(2006)
Mapping the domains of CD134 as a functional receptor for feline immunodeficiency virus.
in Journal of virology
Willett BJ
(2008)
Chemokine receptors and co-stimulatory molecules: unravelling feline immunodeficiency virus infection.
in Veterinary immunology and immunopathology
Willett BJ
(2006)
Differential utilization of CD134 as a functional receptor by diverse strains of feline immunodeficiency virus.
in Journal of virology
Willett BJ
(2013)
The virus-receptor interaction in the replication of feline immunodeficiency virus (FIV).
in Current opinion in virology
Description | We demonstrated that feline immunodeficiency virus variants emerge that escape neutralisation and show altered receptor usage. Variants that have switched receptor usage fail to establish infection when transmitted in a synthetic quasispecies, indicating that the variants that should be used in vaccines should have the transmission phenotype of receptor usage. Furthermore, the receptor usage switch observed following experimental infection has been documented also in natural infection |
Exploitation Route | Veterinary vaccine development (companion animal species) |
Sectors | Healthcare Pharmaceuticals and Medical Biotechnology |
Description | Findings have informed new avenues for vaccine development against feline immunodeficiency virus(FIV) and we have a project funded by a pharmaceutical company to develop an improved FIV vaccine- this is being tested now. |
First Year Of Impact | 2013 |
Sector | Pharmaceuticals and Medical Biotechnology |
Impact Types | Economic |
Description | CPD courses and lectures at veterinary conferences |
Geographic Reach | Multiple continents/international |
Policy Influence Type | Influenced training of practitioners or researchers |
Description | EMEA Special Advisory Group |
Geographic Reach | Asia |
Policy Influence Type | Participation in a guidance/advisory committee |
Description | Member of Veterinary Policy Group British Veterinary Association |
Geographic Reach | National |
Policy Influence Type | Implementation circular/rapid advice/letter to e.g. Ministry of Health |
Impact | Change in policy surrounding the control of TB in cattle has an economic impact on the agriculture industry. |
Description | Vaccination guidelines for feline virus infections |
Geographic Reach | Multiple continents/international |
Policy Influence Type | Participation in a guidance/advisory committee |
Impact | Educates veterinarians across Europe providing recommendations for the appropriate usage of vaccination in cats to prevent disease in cats as well as humans (e.g. zoonotic infections such as Rabies) |
Description | BBSRC Project Grant (Control of feline immunodeficiency virus infection - resubmission) |
Amount | £225,411 (GBP) |
Funding ID | BB/D008425/1 |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 03/2006 |
End | 02/2009 |
Description | Centre for Integrated Virology |
Amount | £5,259,366 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 07/2010 |
End | 07/2015 |
Description | Commercial research support |
Amount | £137,000 (GBP) |
Organisation | Kyoritsu Seiyaku Corporation |
Sector | Private |
Country | Japan |
Start | 09/2012 |
End | 09/2016 |
Description | Consumables for studentship |
Amount | £137,000 (GBP) |
Organisation | Zoetis |
Sector | Private |
Country | United States |
Start | 09/2012 |
End | 09/2015 |
Description | DEFRA award |
Amount | £207,288 (GBP) |
Organisation | Department For Environment, Food And Rural Affairs (DEFRA) |
Sector | Public |
Country | United Kingdom |
Start | 09/2011 |
End | 03/2015 |
Description | Faculty studentship |
Amount | £39,085 (GBP) |
Organisation | University of Glasgow |
Sector | Academic/University |
Country | United Kingdom |
Start | 09/2006 |
End | 09/2009 |
Description | ICP studentship |
Amount | £147,932 (GBP) |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 09/2012 |
End | 09/2016 |
Description | Integrated Training Fellowship for Veterinarians |
Amount | £381,252 (GBP) |
Organisation | Wellcome Trust |
Department | Wellcome Trust Research Training Fellowship |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 09/2009 |
End | 09/2016 |
Description | Wellcome Trust Programme Grant |
Amount | £877,249 (GBP) |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 09/2008 |
End | 09/2014 |
Description | Zoetis |
Amount | £56,000 (GBP) |
Organisation | Pfizer Ltd |
Sector | Private |
Country | United Kingdom |
Start | 09/2012 |
End | 09/2016 |
Title | Plasma samples from vaccinates and controls |
Description | Blood samples from vaccinated cats that resisted challenge with FIV |
Type Of Material | Biological samples |
Year Produced | 2006 |
Provided To Others? | Yes |
Impact | Development, optimization and validation of assay for FIV neutralizing antibodies |
Description | Analysis of Brazilian isolates of FIV |
Organisation | Universidade de São Paulo |
Country | Brazil |
Sector | Academic/University |
PI Contribution | Hosted PhD student in our laboratory |
Collaborator Contribution | Publication- PMID 20084530 |
Impact | Publications- PMID 20084530 and 21619902 |
Start Year | 2009 |
Description | Pathogenesis of natural FIV infection |
Organisation | Purdue University |
Country | United States |
Sector | Academic/University |
PI Contribution | Our aim was to relate clinical findings to laboratory parameters, including FIV load, CD4+ T cell count, viral Env sequence evolution and receptor usage phenotype to determine potential markers of disease progression in naturally acquired FIV infection. We conducted all of the laboratory analyses. |
Collaborator Contribution | Blood samples were collected from naturally infected cat by our partners and dispatched to us at 6 monthly intervals. Post mortem data was made available when cats died. |
Impact | 4 publications, 2 in press in Retrovirology, one in press in J. Gen. Virol. and one under revision for J. Gen. Virol. |
Start Year | 2010 |
Title | Test for FIV neutralizing antibodies |
Description | A quantitative test for neutralizing antibodies against feline immunodeficiency virus infection is being used to understand the protective immune response induced by vaccination against feline immunodeficiency virus using the commercial Fel-0-Vax vaccine |
Type | Support Tool - For Medical Intervention |
Current Stage Of Development | Initial development |
Year Development Stage Completed | 2009 |
Development Status | Under active development/distribution |
Impact | Identification of major neutralizing determinant on the Env of feline immunodeficiency virus |
Description | Board member of European Advisory Board Cat Diseases |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Recommendations for both veterinary practitioners and the lay public are disseminated through the European Advisory Board on Cat Diseases (http://www.abcd-vets.org/), of which the PI is an active member Following these recommendations will lead to an improvement in feline health and welfare |
Year(s) Of Engagement Activity | 2006,2007,2008,2009,2010,2011,2012,2013,2014 |
URL | http://www.abcd-vets.org/ |
Description | Build a Virus Activity |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | Yes |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | Engaged children and their parents, informing them about viruses and the diseases they cause. Further requests eg activity used for scouts and guides visiting the U of Glasgow |
Year(s) Of Engagement Activity | 2013,2014 |
Description | Glasgow Science Centre PCR workshop |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Schools |
Results and Impact | Engaged final year students, provided careers advice for those wishing to pursue a career in science Students very enthusiastic, excellent feedback |
Year(s) Of Engagement Activity | 2012,2013,2014 |
Description | Keynote address |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other academic audiences (collaborators, peers etc.) |
Results and Impact | Keynote speeches sparked questions and discussions of potential avenues for future collaborative research Publication of abstract in preceedings |
Year(s) Of Engagement Activity | 2007,2011,2012,2014 |
Description | Plenary ABCD Rome 2007 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other academic audiences (collaborators, peers etc.) |
Results and Impact | Update on current state of play of development of an AIDS vaccine using the feline immunodeficiency virus as a model publication of FIV guidelines in veterinary publication and online at www.abcd-vets.org |
Year(s) Of Engagement Activity | 2007,2008 |
Description | School visit- Wellington |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | One of our reserach group was guest of honour at The Wellington School (Ayr) Sports Day in June 2006; she was invited as both a veterinarian in academia and an international marathon runner. In the morning she spent time with some of the senior pupils talking about careers and the afternoon was spent cheering on pupils in the games Increased awareness of careers in science amongst school pupils |
Year(s) Of Engagement Activity | 2006 |
Description | Science Media Centre |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | Yes |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | Science Media Centre (Royal Institution of Great Britain) is a pool of experts available to brief the media on the "science behind the story", for example ensuring the veracity of press coverage in the handling of swine influenza by the media. improve public understanding of science |
Year(s) Of Engagement Activity | 2008,2009,2010,2011,2012,2013,2014 |
Description | Website |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | An overview of our work is available at all times from our laboratory web site (http://www.gla.ac.uk/vet/retrovirus/). General advice for owners of FIV-infected cats is available on our project website at http://www.fivprognosis.org/. Increases awareness among veterinarians and public of our research |
Year(s) Of Engagement Activity | 2006,2007,2008,2009,2010,2011,2012,2013,2014 |
URL | http://www.gla.ac.uk/vet/retrovirus/ |