Marek’s Disease Virus

1. Marek’s Disease Virus (And correlation of resistance to Marek’s disease virus with the chicken B21 haplotype)

2. What is Marek’s Disease? • A highly contagious infection in chickens caused by a specific herpes virus that results in a rapidly fatal polyclonal lymphoma.

3. What is Marek’s disease virus? • A herpes virus – genome is double stranded, linear DNA • May be oncogenic; i.e. it may be capable of causing cancer

4. What kinds of viruses are oncogenic? • RNA viruses – Of the RNA viruses, only the retroviruses are oncogenic. • Acute transforming retroviruses carry in their own genome the gene that causes the development of cancer (see following slides). • Chronic transforming retroviruses integrate next to a host cell gene to turn on its expression, and this is what causes the development of cancer (see following slides). • DNA viruses – Many different DNA viruses are capable of being oncogenic.

5. Examples of chronic and acute transforming RNA viruses. Acute Chronic

6. How chronic retroviruses act

7. How do Chronic Retroviruses Transform Animal Cells?

8. Insertional activation

9. How acute transforming viruses are thought to have formed

10. Oncogenesis requires integration of the whole viral cDNA into host cell DNA. Integration is random and is required for viral replication. Oncogenesis requires integration of whole or part of the viral genome into the host cell DNA. Integration is random, but is not required for viral replication. How are RNA oncogenic viruses different from DNA oncogenic viruses?RNA DNA What virus does this remind you of?

11. Oncogenesis occurs when the virus infects its normal permissive host cells. Permissive cells are cells in which there is a productive infection, i.e., cells in which new virus is produced. Oncogenesis occurs when the virus infects a non-permissive host cell, i.e., a cell that lacks something required for viral replication. How are RNA oncogenic viruses different from DNA oncogenic viruses?RNA DNA

12. In acute transforming RNA viruses, the genes that are involved in the development of cancer are normal or modified cellular genes that have been permanently incorporated into the viral RNA genome. They are not viral genes, nor are they required for viral replication. The genes are usually genes that are involved in cell growth control. The genes that are involved in the development of cancer are normal viral genes that are required for viral replication. The genes involved are normally genes whose products complex with cellular tumor suppressor gene products to inactivate their function. How are RNA oncogenic viruses different from DNA oncogenic viruses?RNA DNA

13. Marek’s disease viruses cause three types of infection • Productive infection • Non-productive infection • Long latency • Transforming following short latency

14. What types of infections does Marek’s disease virus cause? • Productive infection – A productive, lytic infection occurs in cells other than lymphocytes.This leads to cell death and the development of necrotic lesions. • This type of infection is caused by both oncogenic and non-oncogenic variants of Marek’s disease virus.

15. What types of infections does Mareks disease virus cause? • Non-productive infections EITHER • Latent infection by a non-oncogenic serotype or variant • occurs predominantly in T lymphocytes. No virus is produced, and there are no visible symptoms. OR • Transforming infection by an an oncogenic serotype • occurs predominantly in T cells and is characterized by a polyclonal T cell lymphoma. No new viruses are produced, but there are visible symptoms. The malignant cells infiltrate • the peripheral nerves and spinal cord leading to paralysis • the iris, leading to blindness • and the skin, leading to skin lesions.

16. What is the difference between a monoclonal and a a polyclonal T cell lymphoma? • A monoclonal lymphoma would result from the proliferation of a single T cell that became malignant. • A polyclonal lymphoma would result from the proliferation of several different T cells, each having become independently malignant from infection by the Marek’s disease virus.

17. Lymphoma, and leukemia, are both cancers of white blood cells.What is the difference? • In a lymphoma, the malignant cells originate in tissues other than the bone marrow (i.e., the lymph nodes, spleen, thymus, liver, etc.) • In a leukemia, the malignant cells originate in the bone marrow.

18. How does Marek’s disease virus cause a lymphoma? • An oncogenic variant of the virus enters through the respiratory route. • An early productive infection occurs in non-lymphocytic cells. (At this stage, virus can spread rapidly through a chicken population.) • The virus particles enter the lymphoid organs and causes short nonproductive latent infections, mainly in T cells. • Nonproductive infection of these T lymphoid cells leads to lymphoma formation in each infected T cell, giving rise to a polyclonal lymphoma.

19. What viral proteins are involved in the development of the malignant lymphoma? • A viral transcriptional activator that transactivates both viral and cellular genes may be involved. • A viral protein may bind the tumor suppressor protein, p53, leading to entry of the cell into the cell cycle, causing it to multiply when it shouldn’t. • A viral protein may block signal-induced apoptosis, causing the cell to survive longer than usual and replicate.

20. What are the MHC genes of chickens called and how are they related to resistance to Marek’s disease virus? • Class I genes are called B-F and they encode MHC molecules found on the surface of all nucleated cells. • Class II genes are called B-L and they encode MHC molecules found on the surface of cells involved in immune function. • The B21 haplotype, which maps to the B-F region, appears to confer resistance to Marek’s disease virus. • Remember that the MHC genes are closely linked and are inherited as a haplotype. • The haplotype numbers are assigned to specific combinations of MHC alleles.

21. What are the MHC genes of chickens called and how are they related to resistance to Marek’s disease virus? • There are 2-3 different genes encoding the alpha chains found in the B-F region. • The primers that you are using in the SSCP analysis are consensus primers for the alpha chains in the B-F region, so they will amplify all 2-3 genes in that region. • The chicken DNAs that you are analyzing are homozygous, so you should ideally see 4-6 bands in your analyses.