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Abstract
HIV-1 utilises −1 programmed ribosomal frameshifting to translate structural and enzymatic domains in a defined proportion required for replication. A slippery sequence, U UUU UUA, and a stem-loop are well-defined RNA features modulating −1 frameshifting in HIV-1. The GGG glycine codon immediately following the slippery sequence (the ‘intercodon’) contributes structurally to the start of the stem-loop but has no defined role in current models of the frameshift mechanism, as slippage is inferred to occur before the intercodon has reached the ribosomal decoding site. This GGG codon is highly conserved in natural isolates of HIV. When the natural intercodon was replaced with a stop codon two different decoding molecules—eRF1 protein or a cognate suppressor tRNA—were able to access and decode the intercodon prior to −1 frameshifting. This implies significant slippage occurs when the intercodon is in the (perhaps distorted) ribosomal A site. We accommodate the influence of the intercodon in a model of frame maintenance versus frameshifting in HIV-1.
Highlights
The ability of the ribosome to maintain reading frame fidelity during protein synthesis is fundamental
This observation is consistent with functional studies demonstrating that mutations perturbing −1 programmed ribosomal frameshifting (PRF) dramatically effect replication efficiency of HIV-1
Recent observations indicate that only those mRNAs undergoing frameshifting are packaged into nascent HIV-1 virus particles, emphasising the importance of the PRF element [51], [52]
Summary
The ability of the ribosome to maintain reading frame fidelity during protein synthesis is fundamental. The tightly controlled mechanisms that maintain fidelity can, be superseded by programmed events, one of which is programmed ribosomal frameshifting (PRF) [1]. PRF involves tRNA slippage either 5 ́ (−1) or 3 ́ (+1) relative to the mRNA followed by continued translation in the new reading frame. There is growing recognition of PRF as a regulatory mechanism used by both prokaryotes and eukaryotes ([9,10,11] and references therein). In the HIV-1 mRNA, −1 PRF results in translation of enzymatic domains and determines a specific ratio of enzymes to structural proteins critical for virus infectivity [12], [13]
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