Abstract
The HIV-1 Vif protein is essential for viral fitness and pathogenicity. Vif decreases expression of cellular restriction factors APOBEC3G (A3G), A3F, A3D and A3H, which inhibit HIV-1 replication by inducing hypermutation during reverse transcription. Vif counteracts A3G at several levels (transcription, translation, and protein degradation) that altogether reduce the levels of A3G in cells and prevent its incorporation into viral particles. How Vif affects A3G translation remains unclear. Here, we uncovered the importance of a short conserved uORF (upstream ORF) located within two critical stem-loop structures of the 5′ untranslated region (5′-UTR) of A3G mRNA for this process. A3G translation occurs through a combination of leaky scanning and translation re-initiation and the presence of an intact uORF decreases the extent of global A3G translation under normal conditions. Interestingly, the uORF is also absolutely required for Vif-mediated translation inhibition and redirection of A3G mRNA into stress granules. Overall, we discovered that A3G translation is regulated by a small uORF conserved in the human population and that Vif uses this specific feature to repress its translation.
Highlights
We discovered that human A3G translation is regulated by a small upstream open reading frame (uORF) embedded within its 50 -untranslated region (UTR) and that human immunodeficiency virus type 1 (HIV-1) Vif uses this specific feature to repress A3G translation and target it to stress granules
Using a computational platform capable of identifying RNA regulatory elements (RegRNA 2.0) [50], we identified a terminal oligopyrimidine (TOP) element that we previously excluded from the Vif-mediated translational control of A3G mRNA as the deletion of the 50 -end region did not impact the Vif-mediated translation inhibition [42], and an uORF within the 50 -UTR of the A3G
We previously showed that these two SLs are required for Vif-mediated A3G translation inhibition [42], suggesting this uORF could be involved in translational inhibition
Summary
Early studies demonstrated that Vif is necessary for virus replication in primary lymphoid and myeloid cells ( called non-permissive cells), but is dispensable in a subset of immortalized T cell lines (called permissive cells) [2,3,4]. This characteristic is due to the expression of a dominant inhibitor of HIV-1 replication in non-permissive cells [5,6], later identified as APOBEC3G (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3G), or Biomedicines 2022, 10, 13. A3G belongs to a large family of cytidine deaminases (A3A to A3H) that interfere with reverse transcription by inducing mutations during the synthesis of the viral (-) strand
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