PRNewswire - December 14, 2001

Recipients of the awards are Richard Kornbluth, M.D. Ph.D, University of California, San Diego, for research to facilitate testing of chemical compounds that inhibit HIV integration into human T-cells; Erwann Loret, Ph.D., Institut de Biologie Structurale et Microbiologie, Marseilles, France, for the study of an essential protein in the life cycle of HIV and his contribution to the development of a new class of drugs that may inhibit the viral protein; and Linqi Zhang, Ph.D., Aaron Diamond AIDS Research Center, New York City, for work to improve understanding and testing of protein interactions that will potentially lead to an effective anti-HIV drug that inhibits HIV from fusing with the host cell.

"These researchers show the spirit of scientific excellence and innovation that gave us the wide variety of anti-HIV drugs available today. Breakthroughs in the last decade made possible the prospect of a long and productive life for millions of HIV-infected men, women and children who once faced the rapid onset of horrible illness and near-certain death," said Barney Koszalka, director of GSK's virology division.

"Nonetheless, HIV remains a formidable enemy. The virus hides where drugs can't reach it, mutates and develops resistance to therapies that once were effective, and can rebound after years of lying dormant," Koszalka said. "These grants are given with no strings attached to support scientists who are dedicated to finding novel solutions to the problems of drug-resistance and viral mutation, preventing the spread of the virus, simplifying treatments for patients or otherwise bringing us closer to the end of the HIV pandemic."

The Role of Preintegration Complexes: Strategies to Inhibit HIV Integration

Like all retroviruses, HIV has three enzymes that play a crucial role at different stages in its life cycle. One of these important enzymes is called integrase. There are no approved drugs that inhibit integrase. This enzyme performs an essential intermediate step by incorporating viral DNA into the DNA of the host cell. Once this occurs, the cell can produce more HIV viruses which, in turn, infect other cells in the body. After integration occurs, the only way to eradicate the virus is to destroy the cell.

"If we can find a way to intercept the virus during the integration process, we can stop it before the cell is permanently infected. This is especially important because, once integration takes place, HIV may persist in a latent state for years in some infected cells. This is why people infected with HIV must take anti-HIV medications their entire lives, and it is a major barrier to controlling or curing the disease," said Richard Kornbluth, M.D. Ph.D., Associate Professor of Medicine at the University of California, San Diego, and the VA San Diego Healthcare System.

Dr. Kornbluth received a $75,000 GSK Award for his research into HIV-1 preintegration complexes (PICs), a grouping of molecules that includes the enzyme integrase plus a number of cellular proteins that attach themselves to the core of HIV after the virus penetrates the host cell. The entire PIC moves through a pore in the nucleus of the invaded cell, where integrase inserts genes from the viral DNA and integrates them with the cell's chromosomes.

Dr. Kornbluth's work to develop the first assay sensitive enough to measure the effect of pharmaceutical compounds on PICs was published this month in the Journal of Biological Chemistry. His research has received support from the National Institutes of Health, The University of California, the U.S. Department of Veteran Affairs and the American Foundation for AIDS Research (amfAR).

Measuring the Effects of Pharmaceutical Compounds on Cell Fusion The first step in HIV infection of a human T-cell is a mechanism that attaches and fuses the virus to the host cell. The outer coat of the virus, or viral envelope, contains glycoproteins (gp) that bind to receptors on the surface of host cells. One of these proteins, called gp41, is believed to interact with CD4, a receptor on the surface of T-cells, fuse the two cells and allow the virus to shed its envelope and penetrate the membrane of the human cell.

Inhibiting protein-protein interactions to prevent HIV from fusing with the T-cell is a new area of research. This could stop the virus before it forms DNA, integrates into the host cell and begins manufacturing new HIV cells. The research also is promising in the search for an effective HIV vaccine.

"Development of new classes of drugs that prevent HIV from invading human T-cells may be a breakthrough in preventing HIV from completing the stages in its life cycle that are necessary to infect a cell and create new viruses," said Linqi Zhang, Ph.D., recipient of a $100,000 GSK Drug Discovery and Development Award. Dr. Zhang is staff investigator, Aaron Diamond AIDS Research Center, and Assistant Professor of Medicine, Rockefeller University, New York City. He is developing an assay to test the effects of chemical compounds on gp41 and the mechanisms by which it fuses with the host cell.

"A drug that inhibits the chemical reaction that occurs when HIV fuses with a T-cell might prevent HIV from injecting its genetic material into the host cell," said Dr. Zhang.

"This research is based on our new understanding of HIV entry into the target cells, a mechanism which is also used by influenza, Ebola and respiratory syncytial viruses. We believe that this novel strategy not only will be useful in identifying chemical compounds capable of inhibiting HIV entry, but also will be applicable to fighting other viruses. The research is also promising in the search for an effective HIV vaccine," he said. The research has received support from the National Institutes of Health, the Irene Diamond Fund, the Elizabeth Glaser Pediatric AIDS Foundation, amfAR, the Treatment Action Group and the Gay Men's Health Crisis.

A Promising New Class of Antiviral Agents that Inhibit an Essential Viral Protein

A new antiviral called TDS is being tested by researchers in France to inhibit Tat, a regulatory protein produced by HIV-infected cells. Erwann Loret, Ph.D., Charge de Recherche in the Centre National de la Recherche Scientifique, Institut de Biologie Structurale et Microbiologie, Marseille, France, received a $75,000 GSK Award for his insights into the structure and function of Tat.

"Tat is a promising target for antiviral therapy or the development of an HIV vaccine. It is needed to regulate the expression of viral genes and plays a role in HIV replication," said Dr. Loret.

"However, Tat also has the capacity to cross membranes. Once outside the host cell, Tat can activate other infected cells, even from a distance, and it is instrumental in the spread of immune deficiency to non-infected cells. It also is a factor in the development of AIDS-related illnesses, such as Kaposi syndrome."

GlaxoSmithKline is a pharmaceutical industry leader in HIV research and therapies. The company is engaged in basic research programs designed to investigate new targets to treat HIV.

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