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Random gene expression may drive HIV into hiding

HIV's RNA enters a host cell, it is copied into DNA, and then a little bit of Tat is made before the virus integrates into the host genome.

At this point, Tat must be chemically modified before it can encourage transcription of more HIV, and random thermal fluctuations in the cell can influence if and when these chemical modifications take place.

Because of Tat's positive-feedback loop, "these fluctuations can be amplified and can lead to very different qualitative behaviors," said Arkin.

If the appropriate modifications take place, then the HIV genome is transcribed and the positive feedback loop kicks in. If these Tat modifications don't happen, then HIV ceases to be expressed, and the cell can then possibly enter a latent state.

The significance of fluctuations in expression are dependent on HIV being expressed at a low level in the cell initially, Arkin said. Commonly, it's only when just a few molecules are interacting with each other that random fluctuations can have such a large effect on eventual outcome, he explained.

The researchers hope that understanding the molecular basis of HIV latency will lead to new treatments to slow or stop progression to AIDS. For example, Arkin suggested, the analysis implies that it might be effective to target the chemical modifications that Tat must undergo before it allows more HIV to be made. "When you quantify things and dissect them at this level, it gives you ways of exploring where your most vulnerable places might be."

Commenting on the work in a preview article published in the same issue of Cell, William J. Blake and James J. Collins of the Center for Biodynamics of Boston University, wrote: "The work of Weinberger et. al. represents an important step in moving from studies that elucidate the origins of stochasticity in gene expression to those that investigate the consequences of such molecular noise on cellular function. The authors [present] a scenario in which HIV-
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Source:Howard Hughes Medical Institute


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