Abstract
The essential HIV-1 viral infectivity factor (Vif) allows productive infection of non-permissive cells expressing cytidine deaminases APOBEC3G (A3G) and A3F by decreasing their cellular level, and preventing their incorporation into virions. Unlike the Vif-induced degradation of A3G, the functional role of the inhibition of A3G translation by Vif remained unclear. Here, we show that two stem-loop structures within the 5′-untranslated region of A3G mRNA are crucial for translation inhibition by Vif in cells, and most Vif alleles neutralize A3G translation efficiently. Interestingly, K26R mutation in Vif abolishes degradation of A3G by the proteasome but has no effect at the translational level, indicating these two pathways are independent. These two mechanisms, proteasomal degradation and translational inhibition, similarly contribute to decrease the cellular level of A3G by Vif and to prevent its incorporation into virions. Importantly, inhibition of A3G translation is sufficient to partially restore viral infectivity in the absence of proteosomal degradation. These findings demonstrate that HIV-1 has evolved redundant mechanisms to specifically inhibit the potent antiviral activity of A3G.
Highlights
The viral infectivity factor (Vif) of human immunodeficiency virus type 1 (HIV-1) and related lentiviruses neutralizes members of the APOBEC3 (Apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3) family of restriction factors, allowing productive viral replication in non-permissive cells expressing these factors[1,2,3,4]
Translation assays[40], we previously showed that Vif was able to bind the untranslated regions (UTRs) of A3G mRNA with high affinity and pointed out the importance of A3G 5′-UTR in its translational inhibition by Vif
The HIV-1 Vif protein has been shown to be necessary for efficient viral infection in non-permissive cells by antagonizing the antiviral activity of A3G
Summary
The viral infectivity factor (Vif) of human immunodeficiency virus type 1 (HIV-1) and related lentiviruses neutralizes members of the APOBEC3 (Apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3) family of restriction factors, allowing productive viral replication in non-permissive cells expressing these factors[1,2,3,4]. Among these cytidine deaminases, APOBEC3G (here referred to as A3G), A3F, A3D and A3H efficiently block HIV-1 replication after entry[5,6,7,8,9,10]. The relative importance of the translational inhibition of A3G by Vif, compared to the well-documented A3G degradation, and its impact on viral infectivity remained to be established
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