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

Schlafen proteins are produced in response to interferon signalling, which can be activated by retroviral infection; this study shows that human schlafen 11 inhibits the late stages of HIV-1 production by binding non-specifically to tRNAs, thus preventing the expression of viral proteins. Schlafen 11 targets HIV-1 codons Schlafen proteins are produced in response to interferon signalling, which can be activated by retroviral infection. This study by Michael David and colleagues identifies an antiviral mechanism within the innate immune response in which human schlafen 11 (SLFN11) inhibits viral protein synthesis in cells infected with HIV-1 by means of codon-bias discrimination. SLFN11 is shown to inhibit the late stages of virus production by preventing the expression of viral proteins. It achieves this by binding non-specifically to transfer RNAs; because viral genes have a higher level of rare codons than do the host's genes, translation of viral proteins is preferentially affected. In mammals, one of the most pronounced consequences of viral infection is the induction of type I interferons, cytokines with potent antiviral activity. Schlafen ( Slfn ) genes are a subset of interferon-stimulated early response genes (ISGs) that are also induced directly by pathogens via the interferon regulatory factor 3 (IRF3) pathway 1 . However, many ISGs are of unknown or incompletely understood function. Here we show that human SLFN11 potently and specifically abrogates the production of retroviruses such as human immunodeficiency virus 1 (HIV-1). Our study revealed that SLFN11 has no effect on the early steps of the retroviral infection cycle, including reverse transcription, integration and transcription. Rather, SLFN11 acts at the late stage of virus production by selectively inhibiting the expression of viral proteins in a codon-usage-dependent manner. We further find that SLFN11 binds transfer RNA, and counteracts changes in the tRNA pool elicited by the presence of HIV. Our studies identified a novel antiviral mechanism within the innate immune response, in which SLFN11 selectively inhibits viral protein synthesis in HIV-infected cells by means of codon-bias discrimination.