|Smith, Timothy - Tim|
Submitted to: Cold Spring Harbor Meeting
Publication Type: Abstract Only
Publication Acceptance Date: 5/1/2006
Publication Date: 5/23/2006
Citation: Schaller, T., Ylinen, L.M., Keckesova, Z., Webb, B.L., Smith, T.P., Towers, G.J. 2006. Isolation of the first non-primate trim5-alpha from cattle indicates that trim5-alpha mediated innate immunity to retroviral infection may be widespread among mammals. Proc., 31st Annual Meeting on Retroviruses, Cold Spring Harbor Lab, Cold Spring Harbor, NY, May 23-28, 2006.
Technical Abstract: TRIM5-alpha has recently emerged as an important factor influencing species-specific permissivity to retroviral infection in a range of primates including humans. Old World monkey TRIM5-alpha blocks HIV-1 infectivity and human or New World TRIM5-alpha proteins are inactive against HIV-1 but active against divergent murine (MLV-N) or simian (SIVmac) retroviruses, respectively. No TRIM5 orthologs have previously been described in rodents, supporting the tentative conclusion that the gene represents a primate specific-defense mechanism. Here we identify the first non-primate TRIM5-alpha ortholog, from cattle, and demonstrate significant antiviral activity against divergent retroviruses including HIV-1. Bovine TRIM5-alpha is closely related to primate TRIM5-alpha proteins in the N terminal RING and B-box 2 domains but significantly less homologous in the C terminal B30.2 domain, particularly in the region shown to influence antiviral specificity. Intriguingly, some viruses restricted by bovine TRIM5-alpha, including HIV-1 and MLV-N, are unable to synthesise viral DNA by reverse transcription whereas restricted HIV-2 makes normal amounts of DNA. Bovine TRIM5-alpha is saturated by high doses of restriction sensitive VLP, but in a cell specific way. Infection by HIV-1 VLP can render bovine MDBK cells sensitive to MLV-N but not to HIV-1 infection. Conversely HIV-1 VLP render feline cells expressing bovine TRIM5-alpha sensitive to both MLV-N and HIV-1 infection suggesting that saturation of restriction may involve saturation of a TRIM5-alpha cofactor in some cases. The data support the conclusion that TRIM5-alpha mediated restriction is a more common attribute of mammals than previously appreciated.