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Retroviruses October 5,6,7 2010 Retroviruses Viral RNA Viral DNA (integrated into host genome) Viral mRNA, genome Reverse (retro) transfer of genetic information Usually, well adapted to their hosts Endogenous retroviruses Retroviridae Feline leukemiavirus Oncovirinae Lentivirinae Avian leukosis viruses Feline, bovine, human immunodeficiency viruses Equine infectious anemia virus Spumavirinae “Foamy” agents A retrovirus virion envelope (ENV) p15e gp70 RNA dep. DNA pol (POL) nucleocapsid p27 (GAG) genome (2 copies) The viral genome Long terminal (oncornaviruses) repeat LTR RNA dependant DNA polymerase GAG Group specific antigens (nucleocapsid) POL ENV LTR Envelope proteins (type-specific antigens) All three genes - GAG, POL, ENV - required for replication Replicative cycle receptor uncoating RNA viral dsDNA integrated into host genome blocked receptors ds DNA mRNA proteins pro-virus genomic RNA assembly Interference receptor for FeLV-A FeLV-A FeLV-A infected cell FeLV-B receptor for FeLV-C receptor for FeLV-B blocked receptors for FeLV-A FeLV-C Pseudotypes FeLV-A P FeLV-B P How do oncoviruses cause cancer? Peyton Rouse and the cancer causing chicken virus Rockefeller University 1912 The Rouse sarcoma virus genome LTR GAG POL ENV LTR GAG POL ENV SRC LTR LTR D. Stehelin, H.E. Varmus and J.M. Bishop 1976 DNA related to the transforming gene of avian sarcoma virus is present in normal avian DNA Nature 260:170-173 Retroviruses and cancer Transduction of oncogenes GAG POL LTR LTR src Activation of oncogenes GAG POL ENV LTR myc LTR Inactivation of tumour-suppressors GAG Rb LTR POL ENV LTR Rb Other transduced oncogenes 1. Sis - platelet derived growth factor (PDGF) cDNA by wooly monkey or cat in simian sarcoma and feline sarcoma viruses Sis protein proliferation PDGF receptor Cell transformed by SSV Other transduced oncogenes 2. Erb. Epidermal growth factor receptor transduced by avian erythroblastosis and fibrosarcoma causing viruses ligand binding site kinase domain inhib. phos. site P P stim. phosp. site EGRF receptor P vErb Feline leukemia viruses • Most common infectious cause of death in cats • Cytoproliferative and cytosuppressive diseases • High mortality in persistently infected cats (>80% in 3 yrs) Endogenous and Type A, B, C viruses GAG LTR • Endogenous sequences GAG • Group Type AA LTR • ubiquitous, in all infectious samples, non-virulent • Group Type BB GAG POL ENV LTR POL ENV LTR POL ENV LTR LTR • in 40% of infectious samples, endogenous X FeLV-A, virulent • Group LTR Type CC • in 1% of infectious samples. Derived by mutation from A GAG POL ENV LTR feline sarcoma and acute leukemia viruses • defective viruses that transduce cellular oncogenes GAG LTR POL oncogene LTR Pathogenesis infection by oral route infection by bite replication in tonsils replication in draining lymph node bone marrow thymus protective immune response recovery latency Peyer’s patches inadequate immune response viremia Consequences of viremia cytoproliferative fibrosarcomas cytosuppressive anemia pancytopenia lymphosarcomas leukemias thymic multicentric alimentary immunosuppression secondary infections chronic stomatitis gingivitis non-healing skin lesions respiratory infections Haemobartonella felis Diagnostic tests • • • • Antigen capture ELISA “FeLuke test” (p27) Fluorescent antibody test Virus neutralization PCR Disease progression and diagnostic tests infection by oral route infection by bite replication in tonsils ELISA sometimes + replication in draining lymph node bone marrow thymus protective immune response recovery latency PCR on bone marrow Peyer’s patches inadequate immune response viremia epitheial cells (shedding) ELISA + FAT + Prevention of FeLV infection • Management • Vaccines Management • Multi cat households or breeders – Can spread rapidly – to solve problem • test • isolate + cats • retest – + -> + PI – + -> - consider – - -> + retest 12 weeks later – to maintain • test and quarantine before new introductions • single cat + – retest – inform owner of consequences Vaccination • Inactivated virus or subunits – FeLV-A – FeLV-A, FeLV-B, FeLV-C – FOCMA • • • • Adjuvants Vectored In practical terms only FeLV-A needed Most vaccines have comparable efficacy Evaluation of vaccine efficacy • challenge systems • “preventable fraction” • factors to consider – – – – number in study criteria for persistent infection method of challenge number of controls with persistent infection http://www.inspection.gc.ca/english/anima/vetbio/prod/felchae.shtml A,B A,B,C A,B A,B,C A,B A,B,C A,B,C Considerations for vaccination • risk? • test before vaccination • vaccine site sarcomas Treatment • Antivirals (experimental) • Immunostimulants (may not be effective) Feline immunodeficiency virus (lentivirus) • 1 to 5% of domestic cats infected (older male cats more likely) • 5 sub-types with considerable antigenic variation • May lead to AIDS like disease • High rate of infection in some felids (lions, cheetahs) with no obvious sickness Pathogenesis bite (virus shed in saliva) inapparent in most cats virus infects B-cells, T-cells and macrophages B-cell proliferation (swollen lymph nodes) variable time reversed CD4:CD8 ratios immunodeficiency (opportunistic infections, B-cell lymphomas) Diagnostic test • ELISA (antibody capture) – antibodies (most infected cats have low levels of circulating antigen) – maternal antibodies - false +ves FIV vaccine Cat retroviruses and endangered felids Iberian Lynx http://www.lynxexsitu.es PLoS One. 2009;4(3):e4744. Epub 2009 Mar 9. Equine infectious anemia virus swamp fever (equine lentivirus) • Per-acute (rare) • Acute/chronic • Inapparent - Asymptomatic carriers CFIA - EIA page (fact sheet and stats) Transmission • Blood (>million viruses/ml) – Tack, instruments – Biting insects • Virus in all secretions – venereal – Milk, colostrum – In utero horse fly deer fly Venereal transmission http://www.inspection.gc.ca/english/anima/heasan/disemala/equianem/equianemfse.shtml Tashjian, 1984, JAVMA, 184:282 Transmission by injection of semen from EIA+ and during natural breeding Transmission by injection of colostrum and natural feeding of foals (Insect transmission can not be ruled out) Transmission by insects feeding is interrupted fly feeds uninterrupted virus is inactivated before next blood meal fly bites horse nearby (< 100m) Pathogenesis (chronic infection) anemia virus multiplies in immune leukocytes complexes thrombocytopenia antigenic change Fever and viremia infectious phases Secondary effects of thrombocytopenia petechial haemorrhages edema Slides: Hugh Townsend Asymptomatic carriers infectious phase viremia stress or steroids Diagnostic Tests • Agar gel immunodiffusion (AGID or Coggin’s test) • ELISA kit (replaced AGID, August 2008) • Horse inoculation • Immuno-blot • cELISA Coggin’s test test samples reference positive sera antigen False reactions on Coggin’s test • False positive – Foal with passive antibody (6 months) • False negative – Recently infected horse Excerpts from CFIA Disease Control Manual of Procedures, 1998 (section 7) • Blood (no anticoagulants) collected by accredited vet and tested by accredited laboratory • If accredited vet suspects exposure must inform District vet • If sample positive, the animal, other in-contact susceptible animals and epidemiologically linked animals(30 days) re-bled and sent to The Retrovirology Centre of Expertise, PEI Follow up after lab conformation of a Reactor • • • • Owner notified Premises declared infected, cold brand reactor (R) Clinical examination of all reactors and exposed animals Destruction order for animals showing clinical signs and asymptomatic reactors not isolated • Compensation (up to $2,750) • In contacts or animals pastured in contiguous pastures tested (30 days prior to testing) • Owner’s responsibility and movement restrictions Animal movement restrictions removed when: • Reactor removed • Remaining animals negative on tests 40 days apart – (first test after removal of reactor) Conditions of isolation • • • • • • • • Must be asymptomatic Must not be used for breeding purposes Premises inspected at least 4times/yr unannounced Separated from other susceptible animals Completely fly proof, vestibuled doors Isolation notice posted on door Exercise only in enclosed fly proof arena attached to stable Exercise outside – in enclosed area – if daily high <0oC. – No non-reactors within 200 yards • All bandages, syringes etc. incinerated Pregnant mares and their foals • Remove foal from infected area (under license) not later than 6 months • Moved to place where there are no other susceptible animals • Tested after 40 days in isolation • If positive(maternal antibodies) retested in 4 months • If positive treat as a reactor. CFIA - EIA control program CFIA - EIA page (fact sheet and stats)