Feline Leukemia Virus (FeLV) Notes PDF

Virus Life Cycle 1. Binding 2. Fusion and 7. Assembly & virus entry Budding...

Virus Life Cycle 1. Binding 2. Fusion and 7. Assembly & virus entry Budding 6. Translation Viral RNA 3. Reverse 5. Transcription/ Transcription Viral Genome 4. Integration into (viral polymerase) Production Feline DNA Proviral DNA Viral DNA PCR test for Integrated viral DNA Proviral DNA – Viral DNA inserted into cat genome – Can be detected by PCR Primer 1 Cat DNA LTR gag pol env LTR Cat DNA Primer 2  Viral LTR Drives Expression of Viral Genes Proviral DNA Cat DNA LTR gag pol env LTR Cat DNA Viral Capsid Replication Envelope promoter (p27)/ enzymes proteins structural (SU & TM) proteins Oncogenic Mechanism 1. Viral Insertional Activation of a Cellular Proto-Oncogene Normal gene expression Cellular Promoter Off On Proto-Oncogene Aberrant oncogene expression Cat DNA LTR gag pol env LTR (On) Oncogene Viral Capsid Replication Envelope promote (p27)/ enzymes proteins r structural proteins (SU & TM) Cancer Oncogenic Mechanism 2. Viral Insertional inactivation of a tumor suppressor gene Normal gene expression Cellular Promoter Off On Tumor suppressor Inactivativation of tumor suppression XXXXXXXXXXXXX XXXXXXXXXXXXX Tumo…. LTR gag pol env LTR (On)..suppresso r Viral Capsid Replication Envelope promote (p27)/ enzymes proteins r structural proteins (SU & TM) Cancer  Oncogenic Mechanism 3. Viral Acquisition of Cellular Oncogenes (Transduction) Associated with rapid tumor development. Viruses carrying oncogene can infect new cells (but needs ‘helper’ virus) “Helper” virus Cat DNA LTR gag pol env LTR Catca (FeLV) DNA Viral Capsid Reverse Envelope Helper virus provides viral proteins in promote (p27)/ Transcriptase proteins trans to rescue the defective virus r structural (SU & proteins TM) Defective virus Cat DNA LTR gag pol Oncogene env LTR Cat DNA (FeSV) Viral Capsid Envelope promoter (p27)/ proteins structural (SU & TM) proteins * Oncogenes can be inserted anywhere in the retroviral genome  Viral Genomes Also Change During Replication Viral polymerase (reverse transcriptase) is error-prone Frequent duplications and mutations occur in the LTR and SU envelope protein – Consequence - altered pathogenesis Cat DNA LTR gag pol env LTR Cat DNA Viral Capsid Replication Envelope promoter (p27)/ enzymes proteins structural (SU & TM) proteins  Internal LTR Duplications Impact Pathogenesis Isolated from asymptomatic cats Enhancer 21bp Promoter (typical LTR structure) Isolated from thymic lymphomas Enhancer Enhancer 21bp Promoter (T cell tumors)  Internal LTR Duplications Impact Pathogenesis Isolated from thymic lymphomas Enhancer Enhancer 21bp Promoter (T cell tumors) Isolated from multicentric Enhancer 21bp 21bp 21bp Promoter lymphomas and other non-T cell tumors Summary: Internal LTR duplications are associated with different diseases in different cell types – Triplication of the 21 bp LTR region allows activation by alternate transcription factors.  Viral Genomes Also Mutate During Replication SU Capsid (p27) Viral polymerase is error-prone Frequent mutations occur in LTR and SU protein – Consequences lead to altered Integrase RNA pathogenesis Reverse Transcriptase  SU Protein Responsible for Entry SU protein Viruses use cellular proteins 1. Binding for entry – Receptor use is virus-specific Cellular receptor FeLV binds receptor via SU protein  Subgroup Viruses Use Different Cellular Receptors Subgroups generated from recombination (FeLV B)/mutations (FeLV C) in SU Each utilizes different cellular receptor Only some cells express receptor – related to pathogenesis FeLV-A FeLV-B FeLV-C SU SU SU Plasma Membrane Phosphate transporter Thiamine transporter Heme transporter FeLV Types FeLV A: Mostly associated with immunosuppression. Transmissable, and the main “street” virus. FeLV B: Associated with neoplasia FeLV C: Associated with anemia Chronic FeLV-C Infection Causes Fatal Anemia Receptor for FeLV-C is FLVCR1 – Normal function – heme export – Infection interferes with receptor function – Depletion of erythrocyte precursors Infection with T-Cell-Tropic FeLV Induces Immunodeficiency. (FeLV-FAIDS) T-cell-tropic FeLV arises through mutations/recombination in SU – Binds to same receptor as FeLV-B, but requires co-factor for entry – Co-factor expression restricted to lymphoid cells – T-cells killed upon infection SU Soluble Cellular Co-Factor Receptor Plasma Membrane  FELV Vaccines Probably reduce likelihood of progressive infections, although efficacy studies are often not comparable. Whole Killed (with adjuvant), recombinant subunit (with adjuvant), or recombinant canary pox vector-delivered. Side effects potential of fibrosarcoma. Avoid worst effects by peripheral administration (peripheral to left stifle; tail). Give to high risk cats only  Key Concepts FeLV infection can cause proliferative and degenerative disease in multiple cell types. FeLV molecular biology is intimately linked to pathogenesis. Transmission can be through friendly contact or biting. Exposed cats can have abortive, regressive, or progressive infections. Vaccines decrease likelihood of progressive infections. Type of FeLV test used is situational (time after exposure) and should be repeated as necessary.