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A simple feedback resistor switch keeps latent HIV from awakening

ors found no experimental evidence for oligomerization of Tat; instead, both on and off forms appear to be monomers.

Other studies have shown that Tat is activated by the addition of an acetyl group--a functional group that is frequently added to (acetylation) or removed from (deacetylation) proteins to modify their properties--and that deacetylation inactivates Tat. Based on the known kinetics of both acetylation and deacetylation, the authors postulated that a resistor might exist in the Tat circuit. A simple mathematical model showed that the interconversion of the two forms, coupled with the known rate of breakdown of Tat, was sufficient to encode a resistor that explained Tat circuit shutoff and possibly the stability of HIV's latent state.

In the Tat resistor model, as in the cell, Tat deacetylation occurs at a much faster rate than acetylation. Deacetylated (inactive) Tat can take one of two paths--reconversion in to acetylated (active) Tat, or destruction of the protein by cellular machinery. When the appropriate conversion and destruction rates were fed into their model, activated Tat appeared briefly after a stray burst of transcription but quickly disappeared without breaking viral latency. This prediction of the model was then precisely replicated in cell culture experiments. An array of cell culture experiments perturbing the supposed Tat resistor was then performed. For example, inhibition of the deacetylating enzyme SirT1 induced Tat transcription activation in cells, further supporting the role of Tat acetylation in controlling viral dormancy. Finally, simulations under noisy conditions predicted that this simple resistor system was better able to resist environmental fluctuations than hypothetical oligomer-dependent switches, and cell-sorting experiments confirmed this prediction.

This simple switch, in which the deactivating reaction overpowers the activating rea ction under most circumstances, acts as a "feedback re
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Source:Public Library of Science


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