HIV沉默和激活机制阐明

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Insight into HIV's 'on-off' switch shows promise for therapy, understanding cellular decisions

Researchers at the University of California, San Diego and Oak Ridge National Laboratory have discovered how a genetic circuit in HIV controls whether the virus turns on or stays dormant, and have succeeded in forcing the virus towards dormancy, a finding that shows promise as an avenue for HIV therapy. Their findings are published in the March 16 issue of the journal Nature Genetics.

加利福尼亚大学圣地亚哥分校国立橡树岭研究所的研究人员发现了控制HIV打开和沉默的遗传机制，并且成功的促使病毒沉默。这项发现为HIV的治疗途径提供了新希望。

Leor S. Weinberger, professor of chemistry and biochemistry at UC San Diego, with Michael L. Simpson of Oak Ridge National Laboratory and Roy D. Dar of the University of Tennessee, Knoxville, say that their study shows how a developmental decision between HIV’s two “replication fates” is made. The authors were able to measure the level of “noise” or randomness in HIV gene expression and use this noise to probe how HIV decides to replicate or remain dormant.

加利福尼亚大学圣地亚哥分校的化学与生物化学教授Leor S. Weinberger、国立橡树岭研究所Michael L. Simpson以及田纳西大学Roy D. Dar认为，他们的研究揭示了HIV的在两种不同“复制命运”之间的是怎样决定的。研究者能够测量HIV基因表达的随机性水平，并以此来探测HIV是要复制还是要保持沉默。

This method is somewhat like finding a radio station by honing in on regions with the most static. It provides a new tool for probing cellular, as well as viral, regulation, and for understanding how other biological decisions are made, notably how stem cells choose between different developmental fates.

这种方法就像在最静默的区域通过摩擦来寻找电台一样。它为探测细胞及病毒、调控、研究其它的生物决定如何完成、特别是干细胞在不同的分化命运之间怎样选择提供了一个新的工具。

“It’s significant for two reasons,” said Weinberger. “First, many researchers are interested in determining which cellular processes generate biological noise. We, instead, asked if the cellular noise could tell us anything about HIV and the cell – and it did. What it told us is how a developmental decision is made by HIV.

Weinberger说：“这有两个重要的意义：首先，许多研究人员对于细胞发育过程中的生物学“噪音”感兴趣，而我们想要知道的是这些“噪音”能否告诉我们一些关于HIV和细胞的一些信息，事实上确实是。它告诉我们的是HIV是怎样做出发育决定的。”

“We still don’t understand how developmental decisions are made at the single-cell level -- for example, how a particular stem cell differentiates into many different cell types -- and whether noise can drive this decision. Surprisingly, viruses appear to be good models for understanding this type of cellular decision-making.”

“我们仍然不知道在单个细胞水平这些决定是怎样做出的——例如一个干细胞是怎样分化为各种不同类型细胞的——以及这些‘噪音’能否诱导这些决定。令人惊讶的是，病毒是理解细胞决定形成的理想模型。”

The authors explored the genetic master circuit of HIV, the Tat circuit, and built upon previous work by Weinberger which showed that it did not function like a standard on-off switch (a light switch, for example).

研究者探索了HIV的主要基因回路——Tat，加上Weinberger之前的工作，这些显示它并没有起到像一个标准的开关一样的作用。（就像电灯开关那样）。

Weinberger’s previous work found that the HIV circuit is driven by cellular noise, or random events, which activate the circuit for a limited amount of time before it turns off. In the current study, Weinberger and colleagues were able to exploit this noise in the HIV Tat circuit to measure how long HIV remained activated in the cell, and deduce that the time spent in the active state drove HIV’s decision to destroy the cell or not.

Weinberger之前的研究发现HIV的回路是由细胞的“噪音”或者随机事件所控制的，这些事件在回路关闭之前的短暂时间使其激活。在目前的研究中，Weinberger和他的同事们能够利用HIV的Tat 回路中的“噪音”来检测HIV在细胞内活跃多长时间，从而推断出在活化状态下诱导HIV是否破坏细胞所需要的时间。

Then the researchers increased the levels of the native cellular gene SirT1 (a gene implicated in aging) to reduce the lifespan of the HIV virus and force HIV-infected cells to go dormant. Further studies are now under way in Weinberger’s lab on the feasibility of using this approach for anti-HIV therapy.

接着，研究人员增加了SirT1（一种涉及衰老的基因）的水平来降低HIV的寿命，从而使HIV感染的细胞处于休眠状态。Weinberger实验室目前正在开展关于使用这种途径来进行抗HIV治疗的进一步研究。

Source: University of California - San Diego
来源：加州大学－圣地亚哥分校