PI Perspective #47

December 2008     View PDF     En español

Zinc finger technology takes a step forward

by Paul Dalton

A poster presentation at the joint 2008 ICAAC / IDSA meeting in Washington, DC described results from a recent study using zinc fingers as a possible anti-HIV therapy. Though this approach has not reached human study, these results show some promise by creating lines of CD4 cells that have become permanently resistant to HIV infection. This occurred in lab cultures as well as in mice.

Zinc fingers are a family of proteins that can alter specific genes in a person’s DNA. In this study they were used to change, or mutate, CCR5 (R5) receptors from allowing HIV to enter CD4s. R5 is the more common co-receptor that HIV uses to enter these cells.

A small number of HIV-positive people who naturally resist HIV infection have what is called the R5 delta32 mutation. Those who get this mutation from both parents are generally quite resistant to HIV infection. Those who get it from one parent tend to experience slower progression of HIV disease.

In this study, researchers used a technology to create zinc finger nucleases (R5-ZFNs) to bind to the area of DNA that codes for R5 receptors. In theory, this DNA change would mimic the delta32 mutation explained above. After a one-time exposure to the R5-ZFNs, the mutation would take place; and as those CD4s divide and multiply, the mutation would carry into the new CD4s.

Results showed that more than half the targeted CD4s were affected by the R5-ZFNs. After the mutation in these cells occurred, the CD4s showed resistance to R5 HIV. Then, as these modified CD4s continued to divide over several weeks, the mutations carried over to the new CD4s which also remained resistant to R5 HIV.

Further, these new CD4s multiplied in special mice that lack normal immune systems. The modified CD4s increased more than 2- to 3-times higher in mice with HIV. Beyond that, after 50 days of HIV infection and treatment with R5-ZFNs, the mice showed a 7-fold decrease in viral load compared to mice without modified CD4s.

The ZFN-treated CD4 cells seem to be permanently changed to prevent R5 HIV infection in those CD4s. Also, the modified CD4s and their offspring seemed to function normally beyond resisting R5 HIV. An additional benefit to treating CD4s with ZFN was an increase in CD4 counts, which may better suppress HIV replication.

The hope that this approach offers sounds extraordinarily promising. However, as bright as these data appear, there are still hurdles to overcome. Since this study evaluated its proof of concept with portions lasting only several weeks or barely two months, the long-term effects of genetically altered R5 remain unknown, especially having not been studied in humans. We simply don’t know how these R5-ZFNs could affect or change HIV or even how they could affect a person’s immune system over time. It may be years until this approach is studied in humans.