But how does the virus infect cells lacking the LDL receptor? The researchers explored the hypothesis that VSV lets itself in through more than one receptor – that is, not only through LDL but also through alternative, structurally similar receptors that must all be members of what is known as the LDL receptor family. To test this hypothesis, they conducted experiments with a versatile protein called RAP, which blocks all family members of the LDL receptor (but, oddly, not the LDL receptor itself).
Indeed, when they pretreated cells lacking LDL receptors with the RAP protein, VSV was no longer able to penetrate these cells. In other words, the experiments bore out the hypothesis: VSV gets into cells mainly through the LDL receptor but also through other members of the LDL receptor family.
This new understanding may be of potential importance for the development of VSV-based cancer therapies. In particular, colon cancer cells have high levels of the LDL receptor on their surface, which suggests they could be selectively killed by VSV.
The new findings might also help improve gene therapy, by increasing the number of LDL receptors on the outer membranes of targeted cells – to facilitate the entry of viruses that carry a desired gene. This goal could, for example, be achieved by the anti-cholesterol drugs statins, which cause cells to display more LDL receptors on their surfaces.
Prof. Menachem Rubinstein’s research is supported by the Bernard and Audrey Jaffe Foundation; the Adelis Foundation; and the Florence Blau Charitable Trust. Prof. Rubinstein is the incumbent of the Maurice and Edna Weiss Professorial Chair of Cytokines Research.