The development of drugs to combat HIV depends entirely on our detailed understanding of basic biological processes, such as HIV entry, replication, and assembly. Certainly, the anti-retroviral drugs currently available – nucleoside analogs, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, and a fusion inhibitor – would not exist if it were not for the basic research completed by numerous scientists at public and private institutions throughout the world. And basic research reported this week in the journal Science may eventually be the basis for another anti-retroviral drug.
Researchers in the Molecular Medicine Program at the Mayo Clinic reported this week that a human protein, named p75 or LEDGF, is essential for HIV integration. After entering a cell, the viral genome is converted from RNA to DNA by an essential viral enzyme – reverse transcriptase. This viral DNA then is transported from the cytoplasm into the nucleus of the infected cell. Another essential viral enzyme, integrase, inserts, or integrates, the viral DNA into the chromosomal DNA of the infected cell. After this integration step, new copies of the viral genome and proteins can be produced. Until recently, the integration mechanism was not well understood.
Over the past years, researchers at the Mayo Clinic and other institutions demonstrated that a human protein, p75, plays an important role in integration. P75 binds both to integrase, the viral enzyme, and chromosomal DNA. It was therefore postulated that p75 could function as a tether, physically linking integrase to the target DNA.
To extend this finding, Dr. Eric Poeschla’s group asked a very straightforward question – what happens when p75 is removed from infected cells? As is often true in science, this simple question could not be addressed simply. To remove p75 from cells, the researchers used two somewhat complicated techniques. First, they depleted p75 via an RNAi strategy. In this approach, a small piece of artificially constructed RNA is placed in the cell. This interfering RNA targets the p75 messenger RNA for destruction by a normal cellular process. When the p75 messenger RNA is destroyed, no p75 protein can be produced. Second, the researchers employed a dominant-negative protein approach. Basically, they engineered a version of p75 that, when inserted into a normal cell, would disrupt the function of any native p75. In both cases, the researchers noted that in cells in which p75 was depleted, HIV integration was severely impaired.
Almost certainly, a p75-based anti-retroviral drug will not be available any time soon. In fact, this basic research may never lead to the development of a new anti-HIV therapy. But research like this does provide us with a better understanding of how HIV infects cells. And all advances in the treatment and prevention of HIV/AIDS depend on this basic research.