Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

A simple feedback resistor switch keeps latent HIV from awakening

27.12.2006
Upon entering a cell, a virus often becomes dormant, turning off its genes and laying low until awakened by som e trigger from its environment. When that trigger is pulled, the virus quickly ramps up production of proteins through built-in positive-feedback loops that turn up gene transcription.

(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
Further information:
http://www.plosbiology.org
http://biology.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pbio.0050009

Further reports about: HIV SOM acetylation deacetylation latency transcription

More articles from Life Sciences:

nachricht A novel synthetic antibody enables conditional “protein knockdown” in vertebrates
20.08.2018 | Technische Universität Dresden

nachricht Climate Impact Research in Hannover: Small Plants against Large Waves
17.08.2018 | Leibniz Universität Hannover

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: It’s All in the Mix: Jülich Researchers are Developing Fast-Charging Solid-State Batteries

There are currently great hopes for solid-state batteries. They contain no liquid parts that could leak or catch fire. For this reason, they do not require cooling and are considered to be much safer, more reliable, and longer lasting than traditional lithium-ion batteries. Jülich scientists have now introduced a new concept that allows currents up to ten times greater during charging and discharging than previously described in the literature. The improvement was achieved by a “clever” choice of materials with a focus on consistently good compatibility. All components were made from phosphate compounds, which are well matched both chemically and mechanically.

The low current is considered one of the biggest hurdles in the development of solid-state batteries. It is the reason why the batteries take a relatively long...

Im Focus: Color effects from transparent 3D-printed nanostructures

New design tool automatically creates nanostructure 3D-print templates for user-given colors
Scientists present work at prestigious SIGGRAPH conference

Most of the objects we see are colored by pigments, but using pigments has disadvantages: such colors can fade, industrial pigments are often toxic, and...

Im Focus: Unraveling the nature of 'whistlers' from space in the lab

A new study sheds light on how ultralow frequency radio waves and plasmas interact

Scientists at the University of California, Los Angeles present new research on a curious cosmic phenomenon known as "whistlers" -- very low frequency packets...

Im Focus: New interactive machine learning tool makes car designs more aerodynamic

Scientists develop first tool to use machine learning methods to compute flow around interactively designable 3D objects. Tool will be presented at this year’s prestigious SIGGRAPH conference.

When engineers or designers want to test the aerodynamic properties of the newly designed shape of a car, airplane, or other object, they would normally model...

Im Focus: Robots as 'pump attendants': TU Graz develops robot-controlled rapid charging system for e-vehicles

Researchers from TU Graz and their industry partners have unveiled a world first: the prototype of a robot-controlled, high-speed combined charging system (CCS) for electric vehicles that enables series charging of cars in various parking positions.

Global demand for electric vehicles is forecast to rise sharply: by 2025, the number of new vehicle registrations is expected to reach 25 million per year....

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

LaserForum 2018 deals with 3D production of components

17.08.2018 | Event News

Within reach of the Universe

08.08.2018 | Event News

A journey through the history of microscopy – new exhibition opens at the MDC

27.07.2018 | Event News

 
Latest News

A novel synthetic antibody enables conditional “protein knockdown” in vertebrates

20.08.2018 | Life Sciences

Metamolds: Molding a mold

20.08.2018 | Information Technology

It’s All in the Mix: Jülich Researchers are Developing Fast-Charging Solid-State Batteries

20.08.2018 | Power and Electrical Engineering

VideoLinks
Science & Research
Overview of more VideoLinks >>>