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Programmed ribosomal frameshifting in HIV-1 and the SARS-CoV - PubMed

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Programmed ribosomal frameshifting in HIV-1 and the SARS-CoV

Ian Brierley et al. Virus Res. 2006 Jul.

Abstract

Ribosomal frameshifting is a mechanism of gene expression used by several RNA viruses to express replicase enzymes. This article focuses on frameshifting in two human pathogens, the retrovirus human immunodeficiency virus type 1 (HIV-1) and the coronavirus responsible for severe acute respiratory syndrome (SARS). The nature of the frameshift signals of HIV-1 and the SARS-CoV will be described and the impact of this knowledge on models of frameshifting will be considered. The role of frameshifting in the replication cycle of the two pathogens and potential antiviral therapies targeting frameshifting will also be discussed.

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Figures

Fig. 1
Fig. 1

Proposed stimulatory RNAs at the frameshift sites of HIV-1 and HIV-2. The HIV-1 signal is shown in panels A–E and that of HIV-2 in panel F. (A) Basic hairpin. The original stem-loop proposed by Jacks et al. (1988b) is shown with the slippery sequence UUUUUUA upstream (underlined). The gag reading frame is indicated as triplets. Sites of cleavage by the viral protease within the encoded polypeptides are indicated by arrows. (B) The pseudoknot model of Le et al. (1991). In this model, the two pseudoknot stems are connected by single-stranded loops of three (loop 1) and eight nucleotides (loop 2), respectively. (C) The small pseudoknot model of Du et al. (1996). Here, base-pairing of the spacer region immediately downstream of the slippery sequence allows an alternative pseudoknot to be drawn that does not include the original stem-loop of Jacks et al. (1988b). (D) The triplex structure of Dinman et al. (2002). This model is based on the prediction of Le et al. (1991) (panel B) but includes the formation of four triplexes between the 3′-end of loop 2 and the top of stem 1 (dotted lines). (E) The two-stem helix model of Dulude et al. (2002) is the most favoured. Here, a short extension to the bottom of the original stem-loop is proposed, with an unpaired stretch (GGA) in the 3′-arm of the stem delineating the two-stem regions. (F) The HIV-2 (Rod) gag/pro frameshift signal can be folded to resemble the HIV-1 two-stem helix (panel E; see text).

Fig. 2
Fig. 2

Genomic organisation of HIV-1. Key features of the HIV-1 genome are shown. Non-coding regions include the terminal repeat regions (R) and the 5′- (U5) and 3′- (U3) untranslated regions. The coding regions (not to scale) comprise the gag, pol and env genes common to all retroviruses, plus the HIV-1 accessory genes vif, vpr, tat, rev, vpu and nef. The lower portion focuses on the proteins encoded at and adjacent to the gag/pol overlap. Black triangles indicate cleavage sites recognised by the viral protease (PR), which releases the capsid (CA), p2, nucleocapsid (NC), p1 and p6 (p6Gag) polypeptides from within the portion of the Gag polyprotein shown and the CA, p2, NC, transframe peptide (TFP), p6* (p6Pol), PR and RT (reverse transcriptase) proteins from within the portion of the Gag-Pol polyprotein shown. The site of divergence between the polyproteins encoded by gag and gag-pol is indicated by an arrow (labelled fs [frameshift]).

Fig. 3
Fig. 3

Genomic organisation of the SARS–CoV and the mechanism of translation of open reading frame (ORF) 1b. Key features of the SARS–CoV genome are shown. Untranslated regions (UTRs) flank the genome at both ends. Major ORFs are present in the following order: 5′-replicase (ORF1a, ORF1b), spike (S), envelope (E), membrane (M) and nucleocapsid (N)-3′ (depicted in blue). Other predicted ORFs (in brown) encode proteins of unknown function. ORFs 1a and 1b are translated from the genomic RNA into polyproteins (pps) 1a and 1a/1b. The synthesis of the 1b portion of 1a/1b involves programmed −1 ribosomal frameshifting (−1 RFS). Arrows represent the corresponding polyprotein sites cleaved by the papain-like proteinase 2 (white) and the 3C-like proteinase (grey). The expanded view shows the nucleotide sequence of the overlapping region between ORFs 1a/1b (slippery sequence in red) and the corresponding amino acids of pps 1a and 1a/1b. Tandem-slippage of the peptidyl-tRNAs (codon UUA) and aminoacyl-tRNAs (codon AAC) on the slippery sequence switches the ribosome into the −1 reading frame (frame of ORF 1b) and generates the amino acid sequences depicted.

Fig. 4
Fig. 4

Predicted RNA secondary structures present at the 1a/1b ribosomal frameshifting signals of the SARS Co-V and IBV. (A) SARS coronavirus. Top: predicted secondary structure. The pseudoknot is composed of two double-stranded stems (S1 and S2) connected by a single-stranded loop (L1) and a second loop (L2) which itself folds into a stem-loop of approximately 28 nucleotides (SL1). Numbers correspond to the nucleotide positions in isolate Tor2. Bottom: primary sequence comparisons. The SARS–CoV consensus shows the sequence of 125 isolates (identical in this region). Mutations have been seen in only two isolates (ZJ01 and GD69) and are of 1 or 2 nucleotides (depicted in red) within SL1 or S2. (B) Infectious bronchitis virus. The pseudoknot is composed of two double-stranded stems (S1 and S2) connected by two loops (L1 and L2). Nucleotides of L2 do not obviously base-pair to form a stable stem and were omitted from the graphic. Numbers correspond to the nucleotide position in the Beaudette strain. The “slippery” sequences are underlined.

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