An Expert Review Board, composed of researchers who are leaders in the field of HIV/AIDS, independently judged and selected the award recipients. John A. Bartlett, M.D., professor of medicine at Duke University Medical Center; David D. Ho, M.D., professor at Rockefeller University and scientific director at Aaron Diamond AIDS Research Center; and Michael Saag, M.D., associate professor of medicine and director of the AIDS Outpatient Clinic at the University of Alabama at Birmingham, served on the board this year.
Recipients of the awards are Irwin Chaiken, Ph.D., University of Pennsylvania, Philadelphia, for his work studying the interactions between proteins that allow HIV to recognize and enter a host cell, research that potentially will lead to drugs that prevent the virus-cell fusion process; Nouri Neamati, Ph.D., University of Southern California School of Pharmacy, Los Angeles, for work in identifying the drug-binding site on HIV integrase, which should lead to development of second- and third-generation drugs that inhibit that enzyme; Alan C. Sartorelli, Ph.D., Yale University School of Medicine, New Haven, Conn., for his research on making certain enzyme inhibitors work more effectively; Nan-Sook Lee, Ph.D., Beckman Institute of the City of Hope, Duarte, Calif., for her research using gene therapy as a potential HIV/AIDS treatment; Elias Lolis, Ph.D., Yale University School of Medicine, for his work in attempting to solve likely side effects of some of the experimental entry inhibitor drugs; and Min Lu, Ph.D., Weill Medical College of Cornell University, New York, N.Y., for his research of a drug developed for herpes that may eventually be used for HIV therapy.
"The latest therapies have worked very well in keeping the deadly AIDS virus at bay, but HIV is crafty and continually is mutating and developing resistance to drugs," said Doug Manion, M.D., vice president of clinical development for GSK. "HIV and AIDS therapy research must continually move forward if we are to stay one step ahead of this disease. We feel strongly that the best way to do that is to encourage and support researchers attempting to develop new approaches to therapies."
Preventing HIV From Infecting Host Cells
HIV works by invading a target immune cell in the human body and turning it into an HIV factory, leading to the infection of new host cells, the overwhelming of the immune system, and eventually, AIDS. Ideally, a drug would be developed to prevent HIV from docking on a host cell to begin with, stopping the infection process.
Many researchers are feverishly working toward such a drug. Among them is Irwin Chaiken, Ph.D., who has been awarded $150,000 by GSK for his work. When HIV meets a potential host cell, a series of interactions occurs between the viral proteins and the host cell receptor proteins, leading to the eventual fusion of the virus with the cell. Dr. Chaiken is studying specific protein interactions in that pathway.
"We want to learn how the virus initially sees the host cell, so we can determine how to inhibit its binding to the cell," said Dr. Chaiken, research professor of medicine at the University of Pennsylvania. "Current HIV medications attack enzymes that are being produced once the cell has been infected. If drugs could be developed to prevent the virus from docking on the cell, we could stop the infection process in the earliest stages of cell invasion. This methodology also could have implications for treatment of other viral diseases, such as hepatitis and influenza."
Trying to Stay One Step Ahead of a Mutating Virus
Among the new HIV therapies in the pipeline are integrase inhibitors, which interfere with the enzyme that binds the virus's newly created DNA to the host cell's DNA. Unlike the other two HIV enzymes, protease and reverse transcriptase – for which quite a few drugs already exist – there are no FDA-approved drugs targeting integrase. Integrase appears to be unique to HIV, which makes it a good target because a drug that interferes with it may not be very toxic to the person taking it.
History has shown, however, that within a year or two of patients' taking new drugs, HIV will undoubtedly mutate, leading to resistance. Therefore, researchers are trying to stay one step ahead and develop second- and third-generation integrase inhibitors. But in order to do that, it must be determined where the integrase inhibitors bind at the molecular level. That is the job undertaken by Nouri Neamati, Ph.D., for which GSK has awarded him $100,000. Dr. Neamati is studying an integrase inhibitor currently in human trials.
"Several groups have been working for 10 years to determine the full length crystal structure of integrase, which has proved difficult," said Dr. Neamati, assistant professor of pharmaceutical sciences at the University of Southern California School of Pharmacy. "Once the three-dimensional structure of integrase is solved and once we know to which amino acid drugs currently being study bind, we can develop second- and third-generation drugs."
Making Current Drugs More Effective
Once HIV fuses to a host cell, it is the job of the enzyme reverse transcriptase to copy the virus's RNA into DNA. Among the more than a dozen approved HIV/AIDS drugs are two reverse nucleoside transcriptase inhibitors (NRTIs) known as purine nucleoside analogs. Although they are effective in fighting the virus, the purine NRTIs have a major flaw: the chemical linkage between their two molecular parts, a sugar analog and a purine base, is unstable and therefore susceptible to being broken, both by the acid in a patient's stomach and by an enzyme, called purine nucleoside phosphorylase. When the chemical link is broken, this class of drugs loses its effectiveness.
A cancer specialist, Alan C. Sartorelli, Ph.D., has worked with purine nucleosides for years, as several of them are used as chemotherapeutic therapies for cancer patients. GSK has awarded him $100,000 for his work.
"We have designed and will synthesize purine nucleoside analogs in which the chemical linkage between the sugar analog and the purine base is resistant to stomach acid and purine nucleoside phosphorylase," said Dr. Sartorelli, the Alfred Gilman professor of pharmacology at Yale University School of Medicine. "Hopefully these agents will lead to new drugs that will be more potent and effective at inhibition of the AIDS virus."
Gene Therapy: A New Approach to Treating AIDS?
Still in the very early stages, gene therapy is an exciting area of research in the fight against HIV and AIDS. Researchers are studying a concept, called gene silencing, that has been used in animals and plants. In humans, it's called RNA interference (RNAi). The idea is to interfere with the molecular capability of cells to be infected by HIV by blocking the synthesis of one of the cellular proteins – a coreceptor – that is necessary for HIV entry into human cells, but not necessary for normal functioning of immune cells. A different approach is to interfere directly with the capability of the virus to grow in human cells. Nan-Sook Lee, Ph.D., has been given a GSK award of $50,000 for conducting research in that area.
"Although several types of RNA gene therapies have been developed and shown to inhibit HIV-1 replication in mammalian cell cultures, in many cases they have been ineffective in animals," said Dr. Lee, senior research fellow in the department of molecular biology at the Beckman Research Institute of the City of Hope, Duarte, Calif. "We hope to overcome those obstacles and bring gene therapy for HIV closer to reality."
Overcoming a Therapeutic Dilemma
As noted, entry inhibitors are some of the newer drugs that are being tested. Entry inhibitors aim to interfere with the early process of the virus infecting the host cell. Included in the chain of events that comprise that process is the involvement of a host cell surface protein, CXCR4.
"Blocking CXCR4 is problematic, because research suggests it is necessary for proper immune system function," said Elias Lolis, Ph.D., associate professor of pharmacology at Yale University School of Medicine. GSK awarded Dr. Lolis $50,000 for his research.
Dr. Lolis' research involves attempting to identify molecules, called allosteric agonists, which would allow the use of entry inhibitor drugs while overcoming this problem.
Drugs Developed For Other Diseases May Work Against HIV
Min Lu, Ph.D., is performing structural biology studies to determine how Doxovir
"Existing drug therapy cannot eradicate the virus, and drug-resistant variants are emerging at an alarming rate, making it imperative for new classes of drugs to be discovered to supplement or partially replace existing regimens," said Dr. Lu, associate professor of biochemistry at Weill Medical College of Cornell University.
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. In addition to GlaxoSmithKline's Drug Discovery and Development Award, the company also provides grants to community based organizations that provide services to those whose lives are most effected by HIV.