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Title: Down-regulation of MHC Class I by the Marek's Disease Virus (MDV) UL49.5 Gene Product Mildly Affects Virulence in a Haplotype-specific Fashion

Author
item JAROSINSKI, KEITH - Cornell University
item Hunt, Henry
item OSTERRIEDER, NIKOLAUS - Cornell University

Submitted to: Virology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/22/2010
Publication Date: 9/30/2010
Citation: Jarosinski, K.W., Hunt, H.D., Osterrieder, N. 2010. Down-regulation of MHC class I by the Marek's disease virus (MDV) UL49.5 gene product mildly affects virulence in a haplotype-specific fashion. Virology. 405(2):457-463. Available on-line at: http://www.sciencedirect.com/science/article/pii/S0042682210004319.

Interpretive Summary: Diseases induced by viruses are, in part, due to their ability to evade the natural defense mechanisms of their host. Understanding the mechanisms pathogens use to evade the host’s immune response is critical for developing new vaccine strategies to combat disease and improve animal health. This report describes a gene in the Marek’s disease virus, a cancer-causing virus of poultry, with immune evading function in some but not all strains of chickens. The information is useful to other scientists who are interested in improving vaccine strategies to control this economically important disease of poultry.

Technical Abstract: Marek’s disease is a devastating neoplastic disease of chickens caused by gallid herpesvirus 2 or Marek’s disease virus (MDV), which is characterized by massive visceral tumors, immune suppression, neurologic syndromes, and peracute deaths. It has been reported that MDV down-regulates surface expression of major histocompatibility complex (MHC) class I molecules, although the mechanism has remained elusive. Close relatives of MDV have been shown to down-regulate MHC class I expression through small viral proteins, such as the infected cell protein (ICP) 47 of herpes simplex virus 1 or the unique long (UL) 49.5 proteins of a number of varicelloviruses, including bovine herpesvirus 1 and pseudorabies virus. MDV does not encode ICP47, but harbors a UL49.5 homologue. Therefore, we tested the contribution of MDV UL49.5 protein (pUL49.5) to down-regulation of MHC class I expression. Using in vitro assays, we conclusively showed that MDV pUL49.5 down-regulates MHC class I directly in the absence of other viral gene products. Additionally, we identified the cytoplasmic tail of MDV pUL49.5 as essential for this function. When viruses lacking the cytoplasmic tail of pUL49.5 were tested in vivo, no differences were seen in highly susceptible chickens of the B19B19 MHC class I haplotype with respect to the development of MD, and horizontal transmission compared to wild-type and revertant viruses. In contrast, there was a reduction in pathogenic potential of the deletion viruses in B21B21 chickens that are more resistant to MDV infection. We concluded that the effect of an inability to down-regulate MHC class I on MDV virulence is small but dependent on the MHC class I haplotype.