Mayo Clinic virologists have discovered that a specific human protein is essential for HIV to integrate into the human genome. Their findings show that when HIV inserts itself into a chromosome, a key step that enables it to establish a "safe haven," it requires a specific protein -- LEDGF/p75 (p75). This protein forms a molecular tether between chromosomes and HIV's integrating protein (integrase). If the connection can be disrupted in the future, it might lead to new therapy for HIV or safer methods of gene therapy. The details appear today in the journal Science.
"How an incoming virus co-opts the cell's assistance as it proceeds to establish its permanently integrated state is a fascinating question," says Eric Poeschla, M.D., the Mayo Clinic virologist who led the research. "It's critical to understand this better because permanently integrated viruses in long-lived cells prevent elimination of HIV. In the future, it will be of interest to examine whether HIV's dependence on p75 can be exploited therapeutically."
How They Did It
The researchers started by noticing that p75 "tethers" HIV integrase to human chromosomes like a molecular rope and also protects it from the cell's protein-degrading machinery. While these were provocative findings, what they meant for the whole virus was unclear.
The Mayo team then developed a highly effective version of a technique called "RNA interference" to strip all detectable p75 from human chromosomes. Without its p75 partner, HIV was highly impaired. An intriguing irony is their use of a crippled version of HIV itself, a virus with proven skill in accessing the human genome, to deliver the RNA interference. As a result, human T cells, HIV's main target, became resistant to HIV. Adding back p75 made them vulnerable again. And adding a "dominant-negative" piece of p75 to the mix, a sort of molecular spanner in the works, further impaired the virus (over 500-fold).
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