Implication of TRIMalpha and TRIMCyp in interferon-induced anti-retroviral restriction activities

<p>Abstract</p> <p>Background</p> <p>TRIM5α is a restriction factor that interferes with retroviral infections in a species-specific manner in primate cells. Although TRIM5α is constitutively expressed, its expression has been shown to be up-regulated by type I interferon (IFN). Among primates, a particular case exists in owl monkey cells, which express a fusion protein between TRIM5 and cyclophilin A, TRIMCyp, specifically interfering with HIV-1 infection. No studies have been conducted so far concerning the possible induction of TRIMCyp by IFN. We investigated the consequences of IFN treatment on retroviral restriction in diverse primate cells and evaluated the implication of TRIM5α or TRIMCyp in IFN-induced anti-retroviral activities.</p> <p>Results</p> <p>First, we show that human type I IFN can enhance TRIM5α expression in human, African green monkey and macaque cells, as well as TRIMCyp expression in owl monkey cells. In TRIM5α-expressing primate cell lines, type I IFN has little or no effect on HIV-1 infection, whereas it potentates restriction activity against N-MLV in human and African green monkey cells. In contrast, type I IFN treatment of owl monkey cells induces a great enhancement of HIV-1 restriction, as well as a strain-tropism independent restriction of MLV. We were able to demonstrate that TRIM5α is the main mediator of the IFN-induced activity against N-MLV in human and African green monkey cells, whereas TRIMCyp mediates the IFN-induced HIV-1 restriction enhancement in owl monkey cells. In contrast, the type I IFN-induced anti-MLV restriction in owl monkey cells is independent of TRIMCyp expression.</p> <p>Conclusion</p> <p>Together, our observations indicate that both TRIM5α and TRIMCyp are implicated in IFN-induced anti-retroviral response in primate cells. Furthermore, we found that type I IFN also induces a TRIMCyp-independent restriction activity specific to MLV in owl monkey cells.</p

Human TRIM Gene Expression in Response to Interferons

Tripartite motif (TRIM) proteins constitute a family of proteins that share a conserved tripartite architecture. The recent discovery of the anti-HIV activity of TRIM5α in primate cells has stimulated much interest in the potential role of TRIM proteins in antiviral activities and innate immunity.To test if TRIM genes are up-regulated during antiviral immune responses, we performed a systematic analysis of TRIM gene expression in human primary lymphocytes and monocyte-derived macrophages in response to interferons (IFNs, type I and II) or following FcγR-mediated activation of macrophages. We found that 27 of the 72 human TRIM genes are sensitive to IFN. Our analysis identifies 9 additional TRIM genes that are up-regulated by IFNs, among which only 3 have previously been found to display an antiviral activity. Also, we found 2 TRIM proteins, TRIM9 and 54, to be specifically up-regulated in FcγR-activated macrophages.Our results present the first comprehensive TRIM gene expression analysis in primary human immune cells, and suggest the involvement of additional TRIM proteins in regulating host antiviral activities

Rôle des protéines de la famille TRIM dans l'immunité innée (étude de leur implication dans l'activité anti-rétrovirale des interférons)

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

Lack of endogenous TRIM5alpha-mediated restriction in rhesus macaque dendritic cells.

International audienceRhesus macaques are resistant to infection by HIV-1 as a result of an innate cellular restriction mechanism attributable to the expression of rhTRIM5alpha, a member of the large tripartite motif (TRIM) protein family. TRIM5alpha-mediated restriction, which occurs before reverse transcription through targeting of the HIV-1 capsid, has been identified in a number of macaque primary cells and cell lines and is thought to occur in all macaque cell types. We report, however, that rhesus macaque dendritic cells (DCs) lack TRIM5alpha-mediated restriction and are equally permissive to HIV-1 infection as human DCs. Evidence suggests that, although TRIM5alpha RNA levels are normal in these cells, the protein may be dysfunctional. We propose that abrogation of TRIM5alpha-mediated restriction in DCs, although still operative in cells that replicate HIV-1 (macrophages, T lymphocytes), illustrates the need for innate mechanisms to not inhibit adaptive immune responses to ensure an optimal fight against pathogens

Implication of TRIMalpha and TRIMCyp in interferon-induced anti-retroviral restriction activities-3

as indicated, and stimulated 24 h later with 1000 U/ml of IFN-β for 8 h. Total RNA was extracted and the levels of TRIMCyp mRNA were determined by quantitative RT-PCR and normalized to GAPDH. The mean ± SD of duplicates is shown. . OMK cells were transfected with anti-Luc (diamonds) or anti-TRIMCyp (triangles) siRNA and transduced 48 h later with increasing doses of HIV-1. The percentage of GFP-positive cells was determined by FACS 48 h post-transduction. . Same experiment as in panel B, except that cells were challenged with HIV-1, N-MLV, B-MLV or NB-MLV (at a MOI of 5), following siRNA and IFN-β treatments. The percentage of GFP-positive cells was determined by FACS 48 h post-transduction. Data are from a typical experiment representative of three independent experiments.<p><b>Copyright information:</b></p><p>Taken from "Implication of TRIMalpha and TRIMCyp in interferon-induced anti-retroviral restriction activities"</p><p>http://www.retrovirology.com/content/5/1/59</p><p>Retrovirology 2008;5():59-59.</p><p>Published online 9 Jul 2008</p><p>PMCID:PMC2483995.</p><p></p