Codon-usage-based inhibition of HIV protein synthesis by human schlafen 11

 Li et al. 2012. Nature. 1;491:125-128

Speaker: Wei-Hung Lin(林韋宏)                                  Time: 15:00~16:00, Feb. 20, 2013

Commentator: Shainn-Wei Wang, Ph.D. (王憲威)       Place: Room 601

Abstract

TypeⅠinterferons induce a large spectrum of interferon-stimulated genes (ISGs) to counteract virus infection, but the antiviral functions of many ISGs are unclear. Here the authors studied the function of Schlafen (Slfn) genes, a subset of ISGs, and revealed a novel antiviral mechanism ofSchlafen 11 (SLFN11) for innate immunity. High-level expression of SLFN11 was detected in 293 cells, in contrast of the virus-packaging 293T cells where SLFN11 was almost undetectable. Knockdown of SLFN11 in 293 cells increased, while ectopic expression of SLFN11 in 293T cells inhibited, virion production of retroviruses, including pseudotyped human immunodeficiency virus 1 (HIV-1). Further examining various steps of the retroviral life cycle, the authors found that SLFN11 had no apparent effect on the early steps, such as viral RNA transcription and RNA export. Notably, SLFN11 selectively inhibited synthesis of viral proteins, such as Gag and Nef, but did not affect protein expression of a reporter gene artificially encoded in the viral genome. It is known that genomes of HIV-1 and some other viruses have biased nucleotide composition from human genes, and thus some rare, suboptimal codons are used for translation of viral proteins. SLFN11 did not inhibit protein synthesis of HIV-1 Gag when the viral open reading frame was synonymously optimized for human cells, indicating that SLFN11 inhibits viral protein synthesis on the basis ofcodon-bias discrimination. Using tRNA array and electrophoretic mobility shift assay, the authors further demonstrated that SLFN11 bound tRNAs and counteracted HIV-induced change of tRNA composition¹. Finally, they demonstrated that SLFN11 can inhibit propagation of wild-type HIV in a T cell line. Overall, this study revealed a novel antiviral mechanism targeted to viral codon usage. The underlying mechanism, i.e., how SLFN11 blocks virus-induced modulation of tRNA pool and selectively inhibits viral translation, remains to be elucidated.

References

1.      van Weringh, A. et al. HIV-1 modulates the tRNA pool to improve translation   efficiency. Mol. Biol. Evol. 28, 1827–1834 (2011).