Interfering RNA smuggled into immune cells stops the entry and spread of HIV
Scientists have successfully used a biochemical Trojan horse to smuggle killer sequences of RNA into immune cells to mug invading HIV, stopping infection in its tracks or preventing the virus from entering the cells in the first place.
Priti Kumar from the Harvard Medical School in Boston, US, and colleagues from the US, Korea and Germany, used a technique called RNA interference (RNAi) to protect mice possessing a human immune system from infection by HIV.
RNAi works by using short strands of small interfering RNA (siRNA) to destroy targeted sequences of messenger RNA that are needed to manufacture proteins. It has been known for some time that such an approach can halt the replication of HIV, but it has proved difficult to get the siRNA across the membrane of T-cells, which the virus attacks, because the negatively charged RNA is repelled at the cell membrane.
The research team first neutralised and disguised the siRNA by complexing it with a conjugate consisting of a short peptide chain made of nine positively-charged D-arginine residues and a small antibody that specifically recognises a protein receptor on T-cells.
The team used a special mouse model to test the system. The mice have no native immune system, but can be transplanted with human blood stem cells, which grow into mature human immune cells.
When the siRNA complex is injected into these mice it latches onto the T-cell receptor and is taken up by the cells. Here the siRNA lies in wait for any invading HIV, which it then prevents from replicating by interfering with the manufacture of essential viral proteins. The researchers also used siRNA against another receptor on the surface of the cells that HIV uses to gain entry. This prevented the uptake of the virus into the cell.
’Both prophylactic and therapeutic regimes proved successful,’ says Kumar. ’Apparently the siRNAs kept HIV from entering most T cells and kept it from replicating when it managed to slip inside.’
’Quite a lot of work has been done to design antibodies that are conjugated to packaging polymers or liposomes, but here they have made a much smaller and more elegant conjugate than most previous systems,’ says Mike Gait of the Medical Research Council Laboratory for Molecular Biology in Cambridge, UK. ’There are issues when you move from small animal models to primates or humans but this humanised mouse is an extremely valuable model - and there is no doubt that this is a potentially big step forward.’
et alCell, 2008, DOI: 10.1016/j.cell.220.06.034