retroviruses n.
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  1. Retroviruses October 5,6,7 2010

  2. Retroviruses Viral mRNA, genome Viral DNA (integrated into host genome) Viral RNA Reverse (retro) transfer of genetic information Usually, well adapted to their hosts Endogenous retroviruses

  3. Retroviridae Feline leukemiavirus Oncovirinae Avian leukosis viruses Feline, bovine, human immunodeficiency viruses Lentivirinae Equine infectious anemia virus Spumavirinae “Foamy” agents

  4. A retrovirus virion

  5. The viral genome (oncornaviruses) Long terminal repeat RNA dependant DNA polymerase LTR LTR GAG POL ENV Envelope proteins (type-specific antigens) Group specific antigens (nucleocapsid) All three genes - GAG, POL, ENV - required for replication

  6. Replicative cycle

  7. Interference

  8. Pseudotypes

  9. How do oncoviruses cause cancer?

  10. Peyton Rouse and the cancer causing chicken virus Rockefeller University 1912

  11. LTR LTR SRC GAG POL ENV The Rouse sarcoma virus genome LTR LTR GAG POL ENV

  12. 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

  13. Retroviruses and cancer

  14. 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

  15. Other transduced oncogenes 2. Erb. Epidermal growth factor receptor transduced by avian erythroblastosis and fibrosarcoma causing viruses ligand binding site kinase domain P stim. phosp. site inhib. phos. site P P vErb EGRF receptor

  16. Most common infectious cause of death in cats Cytoproliferative and cytosuppressive diseases High mortality in persistently infected cats (>80% in 3 yrs) Feline leukemia viruses

  17. Endogenous and Type A, B, C viruses Type A Type B Type C

  18. feline sarcoma and acute leukemia viruses • defective viruses that transduce cellular oncogenes GAG POL LTR LTR oncogene

  19. Pathogenesis infection by oral route infection by bite replication in tonsils replication in draining lymph node bone marrow thymus Peyer’s patches protective immune response inadequate immune response latency recovery viremia

  20. Consequences of viremia cytoproliferative cytosuppressive fibrosarcomas anemia pancytopenia lymphosarcomas immunosuppression leukemias thymic secondary infections multicentric chronic stomatitis gingivitis non-healing skin lesions respiratory infections Haemobartonella felis alimentary

  21. Antigen capture ELISA “FeLuke test” (p27) Fluorescent antibody test Virus neutralization PCR Diagnostic tests

  22. Disease progression and diagnostic tests infection by oral route infection by bite replication in tonsils ELISA sometimes + replication in draining lymph node thymus bone marrow Peyer’s patches ELISA + inadequate immune response FAT + protective immune response viremia recovery latency epitheial cells (shedding) PCR on bone marrow

  23. Management Vaccines Prevention of FeLV infection

  24. 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 Management

  25. 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 Vaccination

  26. 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

  27. A,B A,B,C A,B A,B,C A,B A,B,C A,B,C

  28. Considerations for vaccination • risk? • test before vaccination • vaccine site sarcomas

  29. Antivirals (experimental) Immunostimulants (may not be effective) Treatment

  30. 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 Feline immunodeficiency virus (lentivirus)

  31. 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)

  32. ELISA (antibody capture) antibodies (most infected cats have low levels of circulating antigen) maternal antibodies - false +ves Diagnostic test

  33. FIV vaccine

  34. Cat retroviruses and endangered felids Iberian Lynx PLoS One. 2009;4(3):e4744. Epub 2009 Mar 9.

  35. Per-acute (rare) Acute/chronic Inapparent - Asymptomatic carriers Equine infectious anemia virusswamp fever (equine lentivirus) CFIA - EIA page (fact sheet and stats)

  36. Blood (>million viruses/ml) Tack, instruments Biting insects Virus in all secretions venereal Milk, colostrum In utero Transmission horse fly deer fly

  37. Venereal transmission

  38. 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)

  39. Transmission by insects feeding is interrupted fly bites horse nearby (< 100m) fly feeds uninterrupted virus is inactivated before next blood meal

  40. Pathogenesis (chronic infection) anemia virus multiplies in leukocytes immune complexes thrombocytopenia antigenic change infectious phases Fever and viremia

  41. Secondary effects of thrombocytopenia petechial haemorrhages edema Slides: Hugh Townsend

  42. Asymptomatic carriers infectious phase stress or steroids viremia

  43. Agar gel immunodiffusion (AGID or Coggin’s test) ELISA kit (replaced AGID, August 2008) Horse inoculation Immuno-blot cELISA Diagnostic Tests

  44. Coggin’s test reference positive sera test samples antigen

  45. False positive Foal with passive antibody (6 months) False negative Recently infected horse False reactions on Coggin’s test

  46. 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 Excerpts from CFIA Disease Control Manual of Procedures, 1998 (section 7)

  47. 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 Follow up after lab conformation of a Reactor

  48. Reactor removed Remaining animals negative on tests 40 days apart (first test after removal of reactor) Animal movement restrictions removed when:

  49. 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 Conditions of isolation

  50. 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. Pregnant mares and their foals