(In positive feedback, production of something stimulates more production of that thing, resulting in exponential, or faster, growth.) If the viral environment were perfectly regulated and viral gene expression perfectly silenced during latency, this system would be foolproof. But this is almost never the case—there is always noise and always the potential for some low level of erroneous transcription. This poses a problem for the virus—how does it prevent stray transcription from erupting into full-blown activation?
Certain bacterial viruses manage this problem by encoding intricate repressor circuits that efficiently block transcription. But animal viruses, specifically HIV, appear to lack similar repressor circuits. In a new study, published online in the open access journal PLoS Biology, Leor Weinberger and Thomas Shenk propose that some animal viruses, including HIV, regulate their potential for positive feedback and maintain latency by successively modifying and dissipating, or introducing a resistor into, the main activator of transcription.
HIV’s transcriptional activator, the Tat gene, is encoded in the HIV genome. Once Tat is transcribed, it can rapidly increase transcription not only of itself, but also of other genes that ultimately lead to viral replication. Thus, the Tat protein acts like a molecular switch, making it a likely target for regulating latency. In some kinds of molecular switches, the conversion between on and off states is regulated by self-oligomerization, or binding to several other identical molecules. The shape changes induced by binding or unbinding drive the complex into two different stable conformations. But , the authors 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 resistor,” and its general features, the authors suggest, are likely to be found in other systems that must rapidly alternate between two states while resisting noise in the environment. Their model may also provide an explanation for some puzzling observations about Tat and HIV. Tat contains at least two acetylation sites that must both be deacetylated to turn off transcription. The authors propose this requirement may avoid making the off state so easy to reach that the virus remains dormant all the time. This model also helps explain why some HIV patients experience short “blips” of viral activity, despite relatively low viral concentration. According to the authors, these pulses of viral activation may be due either to random increases of Tat activity or to environmental inhibitors of the SirT1 enzyme, such as dihydrocoumarin, a natural flavoring agent found in clover.
Citation: Weinbe rger LS, Shenk T (2007) An HIV feedback resistor: Auto-regulatory circuit deactivator and noise buffer. PLoS Biol 5(1): e9. doi:10.1371/journal.pbio.0050009.
Andrew Hyde | alfa
Symbiotic bacteria: from hitchhiker to beetle bodyguard
28.04.2017 | Johannes Gutenberg-Universität Mainz
Nose2Brain – Better Therapy for Multiple Sclerosis
28.04.2017 | Fraunhofer-Institut für Grenzflächen- und Bioverfahrenstechnik IGB
More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.
Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...
Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.
"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...
The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.
Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...
The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...
Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.
Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...
28.04.2017 | Event News
20.04.2017 | Event News
18.04.2017 | Event News
28.04.2017 | Medical Engineering
28.04.2017 | Earth Sciences
28.04.2017 | Life Sciences