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

Abstract

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) pathway1. 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.

Differential DNA methylation and PM2.5 species in a 450K epigenome-wide association study

“…This method, which accounts for the number of CpG sites and exposures tested, has been widely used in similar studies. [31][32][33] As a result, the adjusted level of significance in the current study was P-value D 9.4£ 10 ¡9 , i.e., 0.05 / (484,613£ 11). After identifying significant CpGs, we further checked whether they were non-unimodal in the dip test, 34 were cross-reactive, 35 or were located within 10 bases of SNPs relevant to European populations.…”

“…42,43 SLFN11, a member of the SLFN family, potently and specifically abrogates the production of retroviruses, e.g., human immunodeficiency virus (HIV-1). 33 Using cells with endogenously high and low SLFN11 expression and siRNA-mediated silencing, Zoppoli et al 44 found that SLFN11 causally determines cell death and cell cycle arrest in response to DNA-damaging agents in cancer cells from different tissues of origin. SLFN11 cg10911913 is located in a region whose function is promoter associated.…”

Caught in translation: innate restriction of HIV mRNA translation by a schlafen family protein

“…Expressing vpx together with HIV-1 has been demonstrated to increase viral production extensively. The results from Li et al [1] add new evidence of an ISG, namely SLFN11, that controls HIV replication. Interestingly, the major function of SLFN11 is proposed to down-modulate HIV-1 mRNA translation.…”

“…Subsequently, the cell produces spliced viral mRNAs that are transcribed into viral proteins using the host machinery. In a recent paper published in Nature, Li et al [1] describe schlafen (SLFN) 11 as a restriction factor for HIV, acting by regulating viral protein synthesis (Figure 1). Expression of SLFN genes was found to be induced by RNA, DNA, and type I interferon (IFN), hence classifying the SLFN proteins as interferon-stimulated genes (ISGs).…”

“…In summary, the study by Li et al [1] has identified a new antiviral ISG, which should be included in the rapidly expanding list of specific innate immune factors restricting HIV replication. Another key question yet to be answered relates to the importance of [1], exerts antiviral activity through a novel mechanism by targeting tRNAs and reducing their cellular abundance, thus interfering with mRNA translation.…”