Editors' ChoiceHIV/AIDS

Knocking Out HIV Infection?

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Science Translational Medicine  19 Mar 2014:
Vol. 6, Issue 228, pp. 228ec50
DOI: 10.1126/scitranslmed.3008867

A genetic mutation in the gene for CCR5, a molecule used by HIV to enter human immune cells, renders these cells resistant to HIV. The small percentage of people who carry these mutations are either resistant to HIV, even if heavily exposed, or have slow progression of disease if infected. This finding was previously exploited when an HIV-infected patient was treated for leukemia with a stem cell transplant from a donor whose cells had this mutation. The patient was apparently cured of HIV and was able to discontinue antiviral drugs. Such treatment is not feasible, however, for most HIV-infected patients because of its risks.

Tebas and colleagues sought to determine whether a technique called gene editing, in which targeted modifications are made in specific genes, could be used to safely create the same result. They enrolled 12 HIV-infected patients in an open-label study. CD4 immune cells—the cells targeted by HIV—were isolated from each patient’s blood. Zinc-finger nucleases—proteins used to cut the cells’ DNA at specific sites in the CCR5 gene—made the gene permanently nonfunctional without affecting the cells’ normal functions. This technique resulted in CCR5 modification in 11 to 28% of cells. The cells were then reinfused into each patient’s bloodstream. One patient had serious side effects: fevers, chills, and pains after the infusion. The modified cells persisted in the blood and rectal tissue of patients, with an average half-life in the blood of 48 weeks. When antiviral drugs were then stopped in six patients, their HIV viral loads increased as expected. However, the modified immune cells depleted at a slower rate than that of the unmodified cells, suggesting that they were protected against infection. Interestingly, in one patient whose cells already carried one mutated copy of the CCR5 gene, the HIV viral load decreased to undetectable levels even before antiviral treatment was restarted.

This study demonstrates that zinc-finger nucleases can be used to genetically modify CD4 immune cells outside of the body and that these cells can be safely infused into HIV-infected patients. By showing that the cells persist and may be more resistant to HIV infection, the study gives hope that this treatment could be effective. Although this study is only the first step in clinical use of this strategy for HIV treatment, its findings could provide the basis for such genetic modification for treatment of numerous diseases.

P. Tebas et al., Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV. N. Engl. J. Med. 370, 901–910 (2014). [Abstract]

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