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RNA packaging and viral assembly

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Cellular restriction and innate immunity

Mobile genetic elements represent a considerable fraction of our genome, and mammals have developed several strategies to restrict the expansion of transposons, retrotransposons and retroviruses. Several restriction factors inhibiting the HIV-1 replication have been identified: TRIM5α, the Tetherin (BST2), SAMHD1, MX2, and several members of the cytidine deaminase family of APOBEC3 (A3). However, retroviruses have acquired the ability to bypass these restriction factors, and some have developed the so-called auxiliary proteins for this one purpose such as Vif (Viral infectivity factor), Vpu, Nef and Vpx (HIV-2 only), which counteract A3, the Tetherin and SAMHD1, respectively. The neutralization of these cellular restriction factors by retroviruses very often involves the hijacking of the cellular proteasomal degradation pathway in response to their ubiquitination.

Mechanism of translational regulation of APOBEC3G by Vif

Recent data have highlighted the important role played by APOBEC3G (Apolipoprotein B mRNA Editing Enzyme-Catalytic polypeptide-like 3G or A3G) and A3F restriction factors in viral replication. These cytidine deaminases account for the phenomenon of retroviral G-to-A hypermutation produced during the synthesis of the (-) strand of the proviral DNA and is lethal for the virus. These restriction factors are only expressed in cells called “non-permissive”, the target cells of HIV-1 (CD4+ T cells, monocytes/macrophage lineage). In response to this defense mechanism, originally directed against endogenous retroviruses, lentiviruses have co-evolved expressing Vif protein. Besides its role in viral assembly (through its RNA chaperone properties), the main action of Vif is to counteract the activity of A3G/3F proteins (Fig. 1):

  • Induction of A3G/3F degradation by the proteasome (recruitment of an E3 ubiquitin ligase by Vif).
  • Inhibition of A3G mRNA translation.
Schematic representation of the two modes of action of Vif on APOBEC3G proteins. On the one hand, by recruiting a CRL-E3 ligase complex, Vif enables the ubiquitination and degradation of APOBEC3G by the proteasome. On the other hand, by interaction with the 5’-untranslated region of APOBEC3G mRNA, Vif reduces the translation of APOBEC3G.
Figure 1: Schematic representation of the two modes of action of Vif on APOBEC3G proteins. On the one hand, by recruiting a CRL-E3 ligase complex, Vif enables the ubiquitination and degradation of APOBEC3G by the proteasome. On the other hand, by interaction with the 5’-untranslated region of APOBEC3G mRNA, Vif reduces the translation of APOBEC3G.

Our team seeks to understand the mechanisms of cellular restriction and specifically the translational inhibition of A3G/A3F by Vif. The understanding of these processes is important from a therapeutic point of view because there inhibition would increase the packaging of A3G/3F proteins into viral particles with a significant decrease in viral infectivity.