A human gene named ATR normally protects people by preventing the replication of cells damaged by radiation or toxic chemicals. 现在, Utah and New York researchers have discovered how a gene in the AIDS virus hijacks the human gene and turns it into a weapon that prevents reproduction of immune-system white blood cells, 使艾滋病患者容易受到致命的感染和癌症.
The new study "puts us a big step closer to understanding how 艾滋病毒 [human immunodeficiency virus] dismantles the immune system,分子生物学家Vicente Planelles说, 犹他大学医学院病理学副教授.
它还为艾滋病和癌症的新型治疗方法带来了希望.
研究ers already knew that an 艾滋病毒 gene named vpr led to the depletion of immune-system white blood cells named CD4+ lymphocytes. 这项新研究表明，vpr通过激活ATR基因来实现这一功能, 在白细胞和所有人体细胞中发现的是什么.
The ATR gene's normal job is to detect genetic damage to cells caused by radiation, 有毒化学品和化疗, 并阻止受损细胞复制，直到它们能够自我修复. Planelles和罗切斯特大学的研究人员说.Y., found evidence that the vpr gene—one of nine genes in the AIDS virus—exploits this normal repair process to stop vital white blood cells from replicating, 从而破坏免疫系统.
研究结果发表在上个月的《大发娱乐提供》上.
The study raises the possibility of treating AIDS-related immune-system damage with medicines that prevent the human ATR gene from being activated by 艾滋病毒's vpr gene.
"We would like to find a method or a substance that would allow us to interfere with the ability of 艾滋病毒 to kill the white blood cells using this mechanism,Planelles说.
It may take five to 10 years to develop medicines to interfere with the human ATR gene, 他说, 但从理论上讲，它们可能比现有的艾滋病药物有很大的优势, which attack 艾滋病毒 but can lose effectiveness when the virus mutates to resist the drugs.
The research also reinforces Planelles' 1999 discovery that the AIDS virus' vpr gene can kill cancer cells in culture. That raises the prospect of developing a drug that mimicks the vpr gene's ability to activate the ATR gene, 从而阻止癌细胞的复制. 他说，至少需要五年时间才能找到这样一种药物.
许多现有的化疗药物会破坏癌细胞中的DNA. The ATR gene senses the damage and stops division of the cancer cells, in effect stopping the cancer.
在新的研究中, Planelles and colleagues did not actually show how the AIDS virus' vpr gene triggers ATR to halt the replication of CD4+ white blood cells, but instead showed how vpr triggers ATR in human cervical cancer cells known as HELA cells, 阻止癌细胞的复制. 癌细胞更容易在实验室中使用, VPR在所有类型的细胞中都是一样的, 无论是白细胞还是癌细胞, Planelles说.
He plans to replicate the study using white blood cells instead of the cancer cells.
Planelles和Mikhail Roshal一起进行了这项研究, a medical student at the University of Rochester; Baek Kim, a Rochester biochemist; Yonghong Zhu, 他以前是罗切斯特大学的研究生，现在在DNAX研究公司工作, 公司. in California; and Paul Nghiem, a Harvard University postdoctoral researcher.
研究艾滋病毒的“致命武器”
vpr基因已被发现多年, but in 1995 Planelles discovered that its role was to act as 艾滋病毒's "lethal weapon" by preventing CD4+ white blood cells from dividing and replicating, 从而使艾滋病患者的免疫系统瘫痪.
Depletion of CD4+ white blood cells is the hallmark of lost immunity in AIDS patients. 健康人体内CD4+白细胞的数量约为1,每微升血液中有000个细胞, but drops below 200 cells per microliter in untreated AIDS patients and climbs to 500 to 1,在接受抗病毒治疗的艾滋病患者中每微升有000个细胞.
“历史上, 很明显，艾滋病毒会杀死白细胞, 但我花了一段时间才弄明白,Planelles说. “大发娱乐还不完全了解. But by 1995, we figured out that the vpr gene was major factor in killing the cells. 事实上, we can use vpr alone in the absence of other 艾滋病毒 DNA [genetic material] or proteins to kill white blood cells. We discovered the way vpr disrupts the life of the cell is by first preventing it from dividing or reproducing and then inducing it to die. 这是一个双重打击机制."
这项新研究揭示了vpr如何触发人类ATR基因, setting off a "cascade" or "pathway" in which other genes and the proteins they help produce work in a chain reaction to stop white blood cells from dividing.
Planelles在2002年搬到犹他州之前曾在罗切斯特大学工作. The University of Rochester has a patent pending on Planelles' discovery that the AIDS vpr gene activates the human ATR gene, 是1996年在哈佛大学发现的吗.
证明ATR基因的作用
确定ATR基因的作用是困难的. A common method of learning what a gene does is to breed a "knockout mouse" in which the gene has been disabled. By seeing what goes wrong with the mouse, scientists can determine the gene's normal function. But the method could not be used for ATR because the gene is essential for cell division and development of an organism. 如果它被敲除，生物体就会死亡.
So Planelles and colleagues used other methods to block the ATR gene and render it unable to help the AIDS virus vpr gene stop cells from replicating:
- 他们使用了一种叫做“基因沉默”的方法来抑制ATR基因.
- 他们将一种失活的ATR突变基因放入癌细胞中, 使这些细胞中的ATR基因失活.
- 他们将药物应用于ATR基因. 一种是LY294002. 另一种是咖啡因，剂量非常高.
In all three cases, interfering with the ATR gene left it unable to help the AIDS virus' vpr gene. 结果，实验中的细胞能够复制. That demonstrated that vpr activates ATR to block cell replication in cells targeted by the AIDS virus.
Caffeine was used in the study because earlier research found that large concentrations of caffeine blocked the ability of chemotherapy drugs to prevent the division of cancer cells grown in the laboratory, 而是让癌细胞复制. 尽管有新的实验, Planelles说 caffeine is unlikely to be used as an anti-AIDS drug because the necessary doses - equivalent to 140 to 280 cups of coffee per day - would damage patients' nervous system.
将这些发现转化为临床和商业上有用的艾滋病治疗方法, scientists must find a drug that interferes with the ATR gene only in white blood cells and without causing serious side effects, 他补充说.
通往毁灭之路的细节
Here is how Planelles outlines the "pathway" by which the AIDS virus vpr gene stops cells from replicating. 他将这一系列事件描述为“一场接力赛，你要传递接力棒,“除了这次, the proteins produced by genes pass the signal that eventually stops replication of cells:
- vpr基因激活ATR基因. 这究竟是如何发生的尚不清楚.
- ATR基因激活了一种名为Chk1的蛋白质.
- Chk1使另一种名为Cdc25C的蛋白质失活.
- Cdc25C使一种名为Cdc2的蛋白质失活.
- 没有活性Cdc2, cells that already have duplicated their genetic material are unable to split into two cells.