|Smith, Timothy - Tim|
Submitted to: Journal of Virology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/8/2006
Publication Date: 8/30/2006
Citation: Ylinen, L.M., Keckesova, Z., Webb, B.L., Gifford, R.J., Smith, T.P., Towers, G.J. 2006. Isolation of an active Lv1 gene from cattle indicates that tripartite motif protein-mediated innate immunity to retroviral infection is widespread among mammals. Journal of Virology. 80(15):7332-7338. Interpretive Summary: Retroviruses are a type of widespread, disease-causing virus whose name comes from the fact that their genome consists of RNA, which is "retro-transcribed" into DNA after infection of the target cell. Examples of retroviruses that cause disease or decreased performance in cattle are the Bovine Leukemia Virus (BLV) and Bovine Immunodeficiency Virus (BIV). Retroviruses that affect humans include HIV, a member of a genus of viruses called lentiviruses that includes the BIV virus. Research in HIV has identified a cellular factor, called TRIM5a, that is a primary determinant of which species can be infected by particular types of viruses. TRIM5a was thought to be specific to primates, since it was found in all species of monkeys studied but not in biomedical model organisms such as mouse and rat. This manuscript describes discovery of the first non-primate TRIM5a-like factor, that is able to defend the host cell from infection by a range of different retroviruses including HIV. At present it has not been determined if the bovine TRIM5a activity is protective against BIV or BLV, but the work described is the important first step to identify cellular factors that may be involved in establishing infection in cattle herds. The effort to clone and sequence the bovine gene for TRIM5a in cattle was performed by the livestock genomics group at USMARC; all of the viral infection work including the HIV portion of the study was performed by the collaborating laboratory of Dr. Greg Towers in London, who researches HIV and related immunodeficiency viruses.
Technical Abstract: Lv1/TRIM5alpha (tripartite motif 5alpha) has recently emerged as an important factor influencing species-specific permissivity to retroviral infection in a range of primates, including humans. Old World monkey TRIM5alpha blocks human immunodeficiency virus type 1 (HIV-1) infectivity, and the human and New World monkey TRIM5alpha proteins are inactive against HIV-1 but active against divergent murine (N-tropic murine leukemia virus [MLV-N]) and simian (simian immunodeficiency virus from rhesus macaque [SIVmac]) retroviruses, respectively. Here we demonstrate antiviral activity of the first nonprimate TRIM protein, from cattle, active against divergent retroviruses, including HIV-1. The number of closely related human TRIM sequences makes assignment of the bovine sequence as a TRIM5alpha ortholog uncertain, and we therefore refer to it as bovine Lv1. Bovine Lv1 is closely related to primate TRIM5alpha 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 Lv1, including HIV-1 and MLV-N, are unable to synthesize viral DNA by reverse transcription, whereas restricted HIV-2 makes normal amounts of DNA. The data support the conclusion that TRIM protein-mediated restriction of retroviral infection is a more common attribute of mammals than previously appreciated.