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.
Highlights
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
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, is able to interfere at both the level of HIV structural protein and Nef synthesis makes it of particular interest [5,6]
Summary
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. Given that these three proteins are expressed from multiply spliced HIV-1 RNAs that all use the Nxf1 export pathway (Fig. 1A), selective repression of Nef expression may require a different mechanism than that outlined by Marsh et al Inhibition of Nef expression was reported to be associated with the accumulation of nef mRNA in cytoplasmic granules that co-stained with markers of stress granules (SGs); these observations led Henao-Mejia et al to suggest that reduced Nef synthesis was due to sequestration in these bodies.
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