Inhibition of HIV-1 gene expression by Sam68ΔC: multiple targets but a common mechanism?
© Cochrane; licensee BioMed Central Ltd. 2009
Received: 11 February 2009
Accepted: 02 March 2009
Published: 02 March 2009
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.
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 . 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 . 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].
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.
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.
- Tang H, Kuhen KL, Wong-Staal F: Lentivirus replication and regulation. Annual Review of Genetics. 1999, 33: 133-170. 10.1146/annurev.genet.33.1.133.View ArticlePubMedGoogle Scholar
- Foster JL, Garcia JV: HIV-1 Nef: at the crossroads. Retrovirology. 2008, 5: 84-10.1186/1742-4690-5-84.PubMed CentralView ArticlePubMedGoogle Scholar
- Stove V, Verhasselt B: Modelling thymic HIV-1 Nef effects. Curr HIV Res. 2006, 4 (1): 57-64. 10.2174/157016206775197583.View ArticlePubMedGoogle Scholar
- Priceputu E, Hanna Z, Hu C, Simard MC, Vincent P, Wildum S, Schindler M, Kirchhoff F, Jolicoeur P: Primary human immunodeficiency virus type 1 nef alleles show major differences in pathogenicity in transgenic mice. J Virol. 2007, 81 (9): 4677-4693. 10.1128/JVI.02691-06.PubMed CentralView ArticlePubMedGoogle Scholar
- Henao-Mejia J, Liu Y, Park IW, Zhang J, Sanford J, He JJ: Suppression of HIV-1 Nef translation by Sam68 mutant-induced stress granules and nef mRNA sequestration. Mol Cell. 2009, 33 (1): 87-96. 10.1016/j.molcel.2008.11.024.PubMed CentralView ArticlePubMedGoogle Scholar
- Marsh K, Soros V, Cochrane A: Selective translational repression of HIV-1 RNA by Sam68DeltaC occurs by altering PABP1 binding to unspliced viral RNA. Retrovirology. 2008, 5: 97-10.1186/1742-4690-5-97.PubMed CentralView ArticlePubMedGoogle Scholar
- Reddy T, Xu W, Mau J, Goodwin C, Suhasini M, Tang H, Frimpong K, Rose D, Wong-Staal F: Inhibition of HIV replication by dominant negative mutants of Sam68, a functional homolog of HIV-1 Rev. Nature Medicine. 1999, 5: 635-642. 10.1038/9479.View ArticlePubMedGoogle Scholar
- Soros V, Valderrarama Carvajal H, Richard S, Cochrane A: Inhibition of Human Immunodeficiency Virus Type 1 Rev Function by a Dominant-Negative Mutant of Sam68 through Sequestration of Unspliced RNA at Perinuclear Bundles. J Virol. 2001, 75: 8203-8215. 10.1128/JVI.75.17.8203-8215.2001.PubMed CentralView ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.