Dock, Invade - Cell Healed
Viruses are usually only too good at getting into our cells. However, when scientists deliberately modify them to carry desired genes for gene therapy, they usually have difficulty getting into the cells where their cargo is needed. Now researchers seem to have overcome this obstacle by bridging the gap between the weighty, less combative viruses. The new technique links the virus and target cells via a bridge consisting of two proteins: the growth factor EGF (epidermal growth factor) and the receptor for a protein found on the avian leukosis virus (ALV). When given to a cell culture, this bridge allowed the virus not only to attach to the cell but also to enter it. The Harvard Medical School researchers describe these findings (abstract) in the June 9 Proceedings of the National Academy of Sciences.
"What's new is that this transport mechanism works efficiently. This gives us, for the first time, the possibility that we can use this method to target any cell type we want," says John Young, Professor for microbiology and molecular genetics. He developed the method in collaboration with student Sophie Snitkovsky.
Most attempts to develop in vivo gene delivery systems have focused on further modifying the virus, for example by incorporating a structure into its envelope that directs the virus to a specific cell type. But these interventions appear to impair the virus' ability to enter cells.
"We wanted to find a method where we preserved the normal interaction between the viral envelope and the cell receptor as much as possible," notes Young. He and Snitkovsky constructed the EGF-ALV receptor protein bridge and applied it to a range of cell types, including those with the normal EGF receptor and other types without. Only those cells with the EGF receptor bound to the molecular bridge.
To determine whether the virus was actually able to penetrate the cells after it had successfully bound, the researchers inserted a resistance gene against the antibiotic neomycin into the virus. These genetically engineered viruses were added to cells. After an incubation period, the scientists then exposed the cells to neomycin.
To the researchers' surprise, colonies formed - evidence that successful infection with the virus had made the cells resistant to neomycin. In fact, a far higher percentage of cells became infected than expected. "This is really quite remarkable. I think jumping around is just a mild paraphrase of our reaction," says Young.
Success may be partly due to the simplicity of the ALV system. Unlike HIV, which uses multiple receptors, ALV appears to enter cells through a single receptor. Thus, while the ALV receptor appears to be uniquely suited to the protein-bridging approach, EGF is just one of many potential protein partners. Young and Snitkovsky suggest the method could be applied to a variety of cell surface markers, including those found in cancer cells.
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