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).
Moreover, the Mayo team showed that each "knot" of the molecular tether was necessary, defining the mechanism in a way an artist would delineate the knots at each end of the rope that links a tetherball to a pole.
"It turns out that the virus needs surprisingly little p75 to integrate," says Dr. Poeschla. "Future studies will want to factor such potential potency into designs of screens for additional key cellular proteins that HIV either appropriates as partners, as in the case of p75, or schemes to evade. Quite a few more likely exist. The challenge is to use the right methods to find them."
How HIV Infects Humans -- Cannot Currently Be Eradicated
Each time HIV reproduces itself, it uses its integrase protein to insert a copy of its genome into a chromosome. That copy becomes a permanent archive of the virus's genetic program, like a tiny file burned onto a computer hard drive. While patients are kept healthy when those copies are "suppressed" with multiple daily antiviral medicines, they are never cured. Stopping the medicines even briefly lets HIV repopulate the body with many millions of copies, like a computer virus spreading around the world from a single infected computer.
The Mayo Clinic team also included Manuel Llano, M.D., Ph.D.; Dyana T. Saenz; Anne Meehan, M.D.; Phonphimon Wongthida; Mary Peretz; William H. Walker; and Wulin Teo. Dr. Poeschla's laboratory is supported by the National Institutes of Health and the John H. Tietze Foundation Research Trust.
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