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United States Department of Agriculture

Agricultural Research Service

Research Project: HOST IMMUNOGENETICS PREDICT CLINICAL DISEASES IN OVINE PROGRESSIVE PNEUMONIA VIRUS INFECTED SHEEP Title: Common promoter deletion is associated with 3.9-fold differential transcription of ovine CCR5 and reduced proviral level of ovine progressive pneumonia virus

Authors
item White, Stephen
item Mousel, Michelle
item Reynolds, James
item Lewis, Gregory
item Hoesing, Lynn

Submitted to: Animal Genetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: December 29, 2008
Publication Date: September 11, 2009
Repository URL: http://www3.interscience.wiley.com/cgi-bin/fulltext/122365607/PDFSTART
Citation: White, S.N., Mousel, M.R., Reynolds, J.O., Lewis, G.S., Hoesing, L.M. 2009. Common promoter deletion is associated with 3.9-fold differential transcription of ovine CCR5 and reduced proviral level of ovine progressive pneumonia virus. Animal Genetics. 40(5):583-589.

Interpretive Summary: CCR5 is a chemokine receptor that draws immune cells to sites of infection and injury, and it also serves as a coreceptor for cellular entry of human immunodeficiency virus (HIV). A human CCR5 coding deletion (termed delta-32) results in strong resistance to HIV infection, and polymorphisms in CCR5 regulatory regions have been implicated in delayed progression to acquired immune deficiency syndrome (AIDS). Both HIV and OPPV are lentiviruses that preferentially infect macrophages, have similar gene orders, and cause lifelong persistent host infection, so CCR5 may have a role in regulating maedi-visna/ovine progressive pneumonia virus (OPPV) infection. The ovine CCR5 genomic sequence was determined, and sequence variants were obtained from the open reading frame and surrounding regulatory sites. One CCR5 variant contained a 4-base deletion within the promoter region that regulates the gene. The two versions of the promoter in animals with one copy of each showed a 3.9-fold transcription difference (P<0.0001). OPPV proviral levels were also measured in 351 naturally exposed Rambouillet, Polypay, and Columbia sheep. Deletion homozygotes showed reduced OPPV proviral levels among these animals (P<0.01). This deletion has not yet been validated for use in marker-assisted selection, so the association with OPPV levels will need to be replicated in additional populations before anyone uses it to select animals for breeding. However, because of the large impact on transcription and because CCR5 has roles in inflammation, recruitment of effector cells, and cell-mediated immunity, this deletion could play a role in the immune control of infection with many diverse pathogens of sheep.

Technical Abstract: CCR5 is a chemokine receptor that regulates immune cell recruitment in inflammation and serves as a coreceptor for human immunodeficiency virus (HIV). A human CCR5 coding deletion (termed delta-32) results in strong resistance to HIV infection, and polymorphisms in CCR5 regulatory regions have been implicated in delayed progression to acquired immune deficiency syndrome (AIDS). Both ovine progressive pneumonia virus (OPPV), also known as maedi-visna, and HIV are macrophage-tropic lentiviruses, have similar genomic structures, and cause lifelong persistent host infection, suggesting CCR5 may have a role in regulating OPPV provirus levels. Therefore, the ovine CCR5 genomic sequence was determined, and polymorphisms were obtained from the open reading frame and surrounding regulatory sites. One CCR5 variant contained a 4-base deletion within a binding site for octamer transcription factors in the promoter region. A test for differential transcription from each allele in heterozygous animals showed a 3.9-fold transcription difference (P<0.0001). OPPV proviral levels were also measured in 351 naturally exposed Rambouillet, Polypay, and Columbia sheep. Deletion homozygotes showed reduced OPPV proviral levels among these animals (P<0.01). The association of this CCR5 promoter deletion with OPPV levels will need to be validated in additional populations before the deletion can be recommended for widespread use in marker-assisted selection. However, because of the large impact on transcription and because CCR5 has roles in inflammation, recruitment of effector cells, and cell-mediated immunity, this deletion may play a role in the control of infection with many diverse pathogens of sheep.

Last Modified: 12/20/2014
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