Control of feline immunodeficiency virus infection - resubmission

Lead Research Organisation: University of Glasgow
Department Name: College of Medical, Veterinary &Life Sci

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

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Addie D (2009) Feline infectious peritonitis. ABCD guidelines on prevention and management. in Journal of feline medicine and surgery

 
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 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 Membership of a guidance 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 Academic/University
Country United Kingdom
Start 08/2010 
End 07/2015
 
Description Commercial research support
Amount £137,000 (GBP)
Organisation Kyoritsu Seiyaku Corporation 
Sector Private
Country Japan
Start 10/2012 
End 09/2016
 
Description Consumables for studentship
Amount £137,000 (GBP)
Organisation Zoetis 
Sector Private
Country United States
Start 10/2012 
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 10/2011 
End 03/2015
 
Description Faculty studentship
Amount £39,085 (GBP)
Organisation University of Glasgow 
Sector Academic/University
Country United Kingdom
Start 10/2006 
End 09/2009
 
Description ICP studentship
Amount £147,932 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 10/2012 
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 10/2009 
End 09/2016
 
Description Wellcome Trust Programme Grant
Amount £877,249 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2008 
End 09/2014
 
Description Zoetis
Amount £56,000 (GBP)
Organisation Pfizer Ltd 
Sector Private
Country United Kingdom
Start 10/2012 
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 University of Sao 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
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
 
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
URL http://www.gla.ac.uk/vet/retrovirus/