- Commentary
- Open Access
Inhibition of HIV-1 gene expression by Sam68ΔC: multiple targets but a common mechanism?
- Alan Cochrane1Email author
https://doi.org/10.1186/1742-4690-6-22
© Cochrane; licensee BioMed Central Ltd. 2009
- Received: 11 February 2009
- Accepted: 02 March 2009
- Published: 02 March 2009
Abstract
Two recent publications have explored the mechanisms by which a mutant of the host protein Sam68 blocks HIV-1 structural protein synthesis and expands its activity to encompass Nef. Although the two studies propose different mechanisms for the responses observed, it is possible that a common activity is responsible. Understanding how this Sam68 mutant discriminates among the multiple viral mRNAs promises to reveal unique properties of HIV-1 RNA metabolism.
Keywords
- Cytoplasmic Granule
- Stress Granule
- Export Pathway
- Sam68 Mutant
- Selective Repression
Commentary
One of the principles underlying the use of any compound or factor as a therapeutic agent is its capacity to selectively affect the target with little or no off-target effects. With this concept in mind, recent reports regarding the ability of a variant of the host factor Sam68 to selectively regulate the expression of several key components of HIV-1 take on particular interest. HIV-1 replication is critically dependent on the expression of its structural proteins, Gag, Gagpol and Env [1]. As a result, any factor able to inhibit expression of these proteins would force the virus into a state akin to latency. In addition, HIV-1 Nef has been implicated as a major player in the pathogenesis of this virus [2, 3], expression of Nef alone in transgenic mice reproducing many aspects of the pathology seen by the intact virus in humans [4]. The recent reports that a mutant of Sam68, Sam68ΔC (lacking the C-terminal nuclear localization signal), is able to interfere at both the level of HIV structural protein and Nef synthesis makes it of particular interest [5, 6].
Understanding regulation of HIV-1 gene expression by Sam68ΔC. (A) Following transcription, HIV-1 RNA undergoes alternative splicing to generate over 40 mRNAs that correspond to unspliced (encoding Gag and Gagpol), singly spliced (to produce Vif, Vpr, Vpu and Env) or multiply spliced (for generating Tat, Rev and Nef) mRNAs. Unspliced and singly spliced viral RNAs are exported to the cytoplasm via exportin-1, which is mediated by Rev, while the multiply spliced RNAs exit using Nxf1. Once within the cytoplasm, Sam68ΔC interacts with the unspliced, singly spliced and nef mRNAs to block their translation by preventing the binding of PABP1 (shown as a small blue circle). In contrast, PABP1 binds to tat and rev mRNAs, and translation is unaffected. (B) A model for the discrimination between tat, rev and nef mRNAs. The process of splicing used to generate the mRNAs encoding Tat, Rev and Nef results in slight variations in 5' sequence, but all the mRNAs encompass the nef reading frame (individual reading frames are illustrated by block arrows). However, translation of the individual reading frames could result in variations in the composition/structure of the mRNA within the common sequence (as represented by the coloured ovals). Such differences in composition/structure of the viral mRNP could serve as means by which Sam68ΔC selectively regulates their expression.
The suggestion that Sam68ΔC can discriminate nef mRNA from that of tat and rev is of particular interest given that these RNAs not only share a common export pathway but are almost identical except for differences in their 5' untranslated regions (Fig. 1B). The determination by Henao-Mejia et al. that sensitivity to Sam68ΔC is due to sequences in the 3'UTR of nef mRNA that are also present in tat/rev mRNAs raises questions about how repression is restricted to nef mRNAs. One hypothesis is based on the position of the different reading frames and the influence of translation on 3' UTR structure/RNP composition. Both tat and rev mRNAs contain reading frames encoding the respective proteins (Tat or Rev) and that of Nef, while nef mRNA has only one reading frame (Fig. 1B). Since translation requires the unfolding of RNA secondary structure as well as disruption of protein-RNA interactions, it is possible that the sequence spanning the Nef reading frame within tat and rev mRNAs could have very different secondary structure and/or RNP composition than nef mRNA. Consequently, repression specificity could be achieved by Sam68ΔC binding to RNPs containing alternative structure/composition in the region common to the three mRNAs. Such a hypothesis is readily testable and will provide important insights into the determinants that specify susceptibility to regulation by Sam68ΔC. Defining the mechanism by which Sam68ΔC selectively inhibits the expression of several key HIV-1 mRNAs will provide important insights into their regulation and potentially lead to new approaches to controlling the pathogenesis of this virus.
Declarations
Acknowledgements
I wish to thank Mark McNally for all of his constructive suggestions in the preparation of this commentary. Research by A.C. is supported by operating grants from the Ontario HIV Treatment Network and the Canadian Institutes of Health Research.
Authors’ Affiliations
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