Science：基因治疗或成为对抗HIV的新武器

marine0425030

在芝加哥举行的抗微生物制剂与化学疗法跨学科会议上，研究者报道了2项小型研究的初步结论，他们通过破坏T细胞表面的CCR5受体来达到抗HIV的目的，CCR5受体是HIV感染T细胞的主要受体。他们希望能借此使患者脱离抗逆转录病毒药物。

研究人员将患者血清中的T细胞分离出，然后通过酶工程学方法对其进行修饰。他们使用锌指核酸酶找出编码CCR5的基因，并将其破坏，最后再将这些修饰后的T细胞回输至患者体内。通过试验，研究者发现经处理后的T细胞约有25%的CCR5受体发生了突变。在部分患者中，经修饰后的T细胞的生存时间超过了6个月。

研究者称，他们并不指望该方法能将HIV从体内完全清除，但是他们希望能通过这种治疗，使患者达到“功能治愈”，也就是说，让患者摆脱抗逆转录病毒药物。

美国北加州大学的病毒学家大卫·马戈利斯称，这种基因治疗仍面临许多问题，他说：“这些数据非常吸引人，也非常鼓舞人心，但仍不够完整。”经人工修饰CCR5基因后发生突变的T细胞比例给马戈利斯留下来非常深刻的印象。

Gene Therapy May Thwart HIV

Jon Cohen

This past year, a Berlin man, Timothy Brown, became world famous as the first—and thus far only—person to apparently have been cured of his HIV infection. Brown's HIV disappeared after he developed leukemia and doctors gave him repeated blood transfusions from a donor who harbored a mutated version of a receptor the virus uses to enter cells. Now, researchers report promising results from two small gene-therapy studies that mimic this strategy, hinting that the field may be moving closer to a cure that works for the masses.

At the Interscience Conference on Antimicrobial Agents and Chemotherapy in Chicago, Illinois, this weekend, researchers reported preliminary results from tests of a novel treatment in 15 HIV-infected people designed to free them from the need to take antiretroviral drugs. The studies, conducted separately on the East and West coasts of the United States, attempt to make the immune system resistant to HIV by crippling a receptor, known as CCR5, on T cells that the virus uses during the infection process. The man who donated blood for Timothy Brown's transfusions had naturally defective CCR5 receptors.

The trial participants had T cells removed from their blood and then modified in the laboratory with a designer enzyme engineered by Sangamo BioSciences in Richmond, California. The enzyme, called a zinc finger nuclease, clips the gene for the CCR5 receptor and disables it. Ten billion modified cells were then reinfused into the participants' bodies, and the new data show that about 25% of cells had the mutant CCR5s. The studies found that modified T cells persisted for more than 6 months in several patients.

In one provocative case reported in Chicago yesterday, a patient who received the gene therapy and then stopped taking antiretroviral drugs had HIV return within a month, as typically happens when people interrupt their treatment. But a few weeks later, the virus began to decline, and it dropped to undetectable levels in concert with evidence that the gene therapy had altered his T cells. "Those kinetics are very different from what I've seen in treatment interruption studies, and we've done many," says Pablo Tebas, an infectious disease clinician at the University of Pennsylvania who heads the East Coast study of six participants. "This patient goes down, way down."

Tebas recognizes that his study is uncontrolled and that they've seen this response in only one patient. What's more, the patient already had a natural advantage because he has a crippled CCR5 gene in one of the two copies he inherited. Tebas suspects that the gene therapy coupled with his natural CCR5 mutation combined to lead to the dramatic result. "This is a very small experiment, and I don't think it's a cure by any means, but the Berlin patient is only one patient, and it changed research priorities," Tebas says. "This shows that there's a correlation between antiviral activity and the proportion of modified cells. It shows a path forward."

Although researchers do not expect the gene therapy to entirely clear HIV from the body, they hope it will create a "functional cure"—in other words, contain the virus to such a powerful extent that people no longer need antiretrovirals.

Virologist David Margolis, who is conducting his own HIV cure studies at the University of North Carolina, Chapel Hill, says many questions remain about the impact of this gene therapy, however. "These data are interesting, and encouraging, but still incomplete," he says. Yet Margolis is "impressed" by the percentage of cells that have the artificially modified CCR5 gene.

Even if this gene therapy proves itself, the cost and technical challenge of the intervention means it likely will have little chance of being used outside of wealthy countries. But Tebas notes that the cost of antiretrovirals also is high and that any calculation would have to balance one against the other.

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http://news.sciencemag.org/biology/2011/09/gene-therapy-may-thwart-hiv