Research press release


Nature Biotechnology

Fingers point way to HIV treatment



機能をもったCCR5を発現する正常なT細胞で、このような天然のウイルス耐性機構を真似ることができないかを調べるため、C Juneたちは、CCR5遺伝子を遺伝子治療の手法によって意図的に破壊した。この方法では、DNAを特異的な塩基配列のところで切断するZnフィンガーエンドヌクレアーゼが利用された。酵素の変異体をつくることによって、ゲノム配列のどれを切断するかを制御することができる。



T cells, a type of white blood cell that is destroyed by HIV, have been made resistant to HIV infection, both in the test tube and in mice, using an enzyme designed to disrupt a specific gene. The results, published online this week in Nature Biotechnology, could lead to a clinical treatment in which the T cells of an HIV-positive individual would be isolated, genetically altered with the enzyme and then returned to the body.

HIV enters T cells by recognizing two different cell-surface receptors?a primary receptor, called CD4, and a co-receptor, such as CCR5 or CXCR4. Rare individuals who are born with mutations in the CCR5 gene lack functional CCR5 molecules on their T cells and are naturally resistant to HIV infection.

To see if this natural mechanism of viral resistance could be mimicked in normal T cells that do express functional CCR5, Carl June and colleagues deliberately disrupted the CCR5 gene using a genetic treatment. The treatment involves zinc-finger endonucleases, enzymes that cut DNA at specific sequences. By making variants of these endonucleases, researchers can control which genomic sequences are cut.

The authors designed a zinc-finger endonuclease meant to target the CCR5 gene and showed that it disrupts this gene in primary human T cells with very high specificity. When a mixture of modified and unmodified T cells was infected with HIV in a culture dish, the modified T cells survived better. Tests in a mouse model of HIV infection revealed that animals transplanted with the modified T cells had lower viral loads and higher numbers of T cells compared with animals that received unmodified T cells.

Ultimately, if clinical trials confirm the positive results in mice reported here, this treatment may be useful for restoring the immune systems of HIV-positive individuals by rendering their T cells resistant to HIV infection.

doi: 10.1038/nbt1410


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