HIV-1 replication and the cellular eukaryotic translation apparatus

Abstract

Eukaryotic translation is a complex process composed of three main steps: initiation, elongation, and termination. During infections by RNA- and DNA-viruses, the eukaryotic translation machinery is used to assure optimal viral protein synthesis. Human immunodeficiency virus type I (HIV-1) uses several non-canonical pathways to translate its own proteins, such as leaky scanning, frameshifting, shunt, and cap-independent mechanisms. Moreover, HIV-1 modulates the host translation machinery by targeting key translation factors and overcomes different cellular obstacles that affect protein translation. In this review, we describe how HIV-1 proteins target several components of the eukaryotic translation machinery, which consequently improves viral translation and replication.

Figure 1

Eukaryotic translation initiation. mRNA maturation and nuclear export precede translation initiation (steps 1 and 2). Once in the cytoplasm, mRNA is activated (step 3) and 43S PIC formation takes place (step 4 to 5). The mRNA recruits the 43S PIC and scanning begins until an initiation codon is detected (step 6). At this point, the 48S initiation complex is formed and the 60S subunit is recruited to form the ribosome 80S complex (step 7 to 9). HIV-1 viral functions important to control the eukaryotic translation initiation are shown. (A) Unspliced and singly-spliced viral mRNAs could be translated due to the ability of the CBC to activate mRNA during translation initiation (green line); (B) HIV-1 protease partially inhibits translation initiation by targeting PABP, eIF3 and eIF4G (red lines); (C) Vpr-induced G2/M arrest indirectly inhibits host protein translation by targeting eIF4E activity (red line); (D) HIV-Tat protein and high concentration of HIV-1 TAR element indirectly promote viral translation by blocking PKR activity (red line). PKR phosphorylates eIF2α to block its recycling for ongoing translation, resulting in a potent translation inhibition of cellular and viral mRNA.

Figure 2

Eukaryotic translation elongation. eEF1A-GTP transports the aminoacylated tRNAs into the A site of the 80S ribosome and eEF1A-GDP is re-activated by eEF1B (step 1). The 80S ribosome-mediated peptide bond formation (step 2) precedes ribosome translocation mediated by eEF2 (step 3). Finally, the ribosome begins another cycle of peptide elongation (step 4). HIV-1 viral functions important to control the eukaryotic translation elongation are shown. (A) HIV-1 Pr55^Gag interacts with eEF1A and induces translation inhibition (red line); (B) HIV-1 Nef protein also interacts with eEF1A and mediates a nucleocytoplasmic relocalization of eEF1A (red line); (C) The HIV-1 RTC recruits eEF1 to stimulate late steps of the HIV-1 reverse transcription process (green line).

Figure 3

The HIV-1 vpu-env bicistronic mRNA. A schematic diagram of the HIV-1 provirus genome is presented along with its primary 9 kb mRNA transcript. The vpu-env bicistronic mRNA is formed after splicing of the 9 kb mRNA. Start codon sequences of both vpu and env ORFs are presented and the upstream ORF that stimulates Env translation is boxed in green.

Figure 4

HIV-1 IRESs. HIV-1 IRES and HIV-1 Gag IRESs are represented. The 43S pre-initiation complex can mediate both cap-dependent and IRES-mediated translation initiation.

Figure 5

HIV-1 Ribosomal frameshift. A schematic diagram of the −1 nucleotide ribosomal frameshift. This process is mediated by a slippery heptanucleotide sequence (UUUUUUA) where the frameshift takes place, and an RNA element called the frameshift stimulatory signal (FSS).