New Discoveries in HIV Research
Over the past twenty years there have been a vast wealth of discoveries in HIV research, perhaps unparalleled in the history of biomedical investigation. Since the early days of the epidemic, scientist's understanding of HIV and the immune system has advanced leaps and bounds. Yet, the fruits of very basic science research do not always show themselves immediately. Certainly the scientific process is far from ideal in translating information learned in the laboratory to therapy and patient care advances at the bedside. Still, advances in basic science have greatly improved the care of people living with HIV. This article will briefly overview a few major discoveries and shed light on a new emerging theory about the role and implications of cholesterol in HIV infection.
The discovery of HIV as the cause of AIDS in the early/mid-1980s and the subsequent ability to grow the virus in large quantities in the laboratory quickly led to the development of the HIV antibody test. The wide scale availability of HIV testing allowed people to learn if they were living with the virus and take health-promoting action. The ability to grow the virus in the laboratory also allowed for the development of drug-screening tests, where compounds could be evaluated rapidly in a test tube to see if they had activity against the virus.
Researchers began efforts to characterize the structure of key enzymes critical for HIV to reproduce. One such effort focused on the protease enzyme, which makes it possible for newly formed particles of virus, made by infected cells, to assemble into a viable and infectious virus. Once the structure of the protease enzyme was identified, scientists began their quest for compounds that could block the activity of protease. By the mid-1990s, several compounds had been selected and brought through the drug testing and approval process. The use of protease inhibitors revolutionized HIV treatment in the developed world.
A similar effort has been underway, with less success, in characterizing the structure of the integrase enzyme and therapies that might inhibit its activity. Integrase is important for helping the virus integrate into the machinery of immune cells, taking over the cell's function and using the cell as an HIV particle production plant of sorts. This field is moving slowly and has been fraught with many disappointments. Only a single integrase inhibitor is undergoing testing in people at this time, and most companies have abandoned their efforts in this area. Still, perhaps one day integrase inhibitors will be added to the arsenal of anti-HIV therapies.
Laboratory work on better understanding HIV and its components have led to the development of a new class of therapies called fusion inhibitors. Pentafuside (also called T-20) is furthest along in development. This approach interferes with a protein on HIV, called gp41, that is critical for HIV to attach to a cell.
In the mid-1990s, an important discovery was made about the role of proteins on a variety of immune cells, called G7 transmembrane proteins. HIV latches onto these proteins and uses them to get inside of a cell. There are a variety of these proteins, notably are ones called CCR5 and CXCR4 (also called fusin). Efforts are underway to find drugs that can bind to CCR5 and CXCR4, effectively putting a bandaid on them that will block the ability of HIV to infect a cell. (Visit Project Inform's Web site or call the hotline for more information on CCR5 and Co-Receptors.)
CCR5 and CXCR4 are called adhesion molecules, because they bind or adhere to particles in the blood and help to transport material across the cell membrane and into the inner workings of a cell. CCR5 and CXCR4 are just a few of many adhesion molecules that are on the cell surface, however, and it's been shown that all major adhesion molecules have interaction with HIV. When adhesion molecules are present on the cell surface, HIV binding to a cell increases from a few hundred to thousands of virus binding to the cell. These molecules not only increase the ability of HIV to bind to the cell, but they also increase the ability of HIV to infect the cell and actually help to transport the virus into the cell. Moreover, when HIV is bound to one of these molecules, it's much more difficult for the immune system to effectively target and neutralize or eliminate it.
In addition to the role that adhesion molecules play in facilitating HIV binding and infection of cells, they also have a key role in allowing infected cells to release new HIV. The virus has to get into the cell in order to take over the machinery of the cell and reproduce, but it also has to get out of cells. Work by Dr. James Hildreth of Johns Hopkins University, and others, have shown that over 90% of HIV budding out of cells occurs at a region of the cell rich in adhesion molecules called lipid rafts. These lipid rafts are important for cholesterol trafficking and also in transporting materials into, out of and throughout cells. Lipid rafts have not only been shown to be important for HIV, but other viruses, such as influenza and measles as well, which also selectively bind and bud from them. Understanding the role of lipid rafts in HIV may have important implication for future directions in AIDS therapies.
Cholesterol is found in all tissues, oils, fats, blood etc. It is a key component of lipid rafts. Hildreth and his team at John Hopkins Medical School conducted a series of experiments to identify the role of cholesterol and lipid rafts in HIV infection.
Using a compound call beta-cyclodexin (BCD), Hildreth was able to change the cholesterol level in cells, eliminating about 90% of the cholesterol in a cell within one hour. Through a collection of laboratory experiments Hildreth's team discovered the following:
Hildreth's work underscores the importance of lipid rafts and cholesterol in HIV infection and budding of cells. Cholesterol depletion of HIV infected cells resulted in the production of non-infectious virus and cholesterol depletion of HIV inactivated the virus. Restoration of cholesterol in the cells or in the virus completely reversed these activities. Hildreth concludes that intact lipid rafts and cholesterol are required for HIV infectivity.
Hildreth's team is particularly interested in applying these discoveries to the invention of a topical microbicide that might be useful in HIV prevention efforts. Topical microbicides are usually creams or gels that could be used as vaginal suppository, perhaps even added to lubricant. The goal is to identify a compound with anti-HIV activity that could disable HIV and prevent sexual/vaginal transmission of the virus. The group at Johns Hopkins University has been exploring the potential of using beta-cyclodexin as an HIV microbicide.
Unlike nonoxynol-9, a much studied topical microbicide, BCD is not toxic to cells, particularly cells in the vaginal tract (called epithelial cells). Animal studies suggest that nonoxynol-9 completely destroys epithelial cells, which are important to protect women from virus infections and other critters that can cause gynecologic complications in women. In this same model, however, BCD showed minimal toxicity to epithelial cells and it significantly inhibited HIV transmission/infection, whether the BCD was simply used to treat vaginal cells or if it was delivered intravaginally.
While cholesterol-depleting approaches may have important implications for HIV prevention and microbicides, there are also potential implications for treatment that have yet to be fully explored and warrant immediate investigation. Dr. Eric Freed of the National Institutes of Health has also conducted laboratory studies of BCD and shows that the anti-HIV activity of BCD is dose dependent (e.g., the higher the dose, the greater HIV is inhibited) and also confirms that BCD is not causing overall toxicity to cells. Dr. Freed has examined a readily available cholesterol-lowering agent, a statin inhibitor called simvastatin (Zocor). Dr. Freed's work suggests that simvastatin can decrease HIV replication/production and posits that the widespread use of statin inhibitor drugs for the treatment of high cholesterol raises the opportunity to explore whether these compounds are useful as anti-HIV agents.
Basic science discoveries about the immune system and HIV often seem esoteric and removed from the real world of people living with HIV. Discoveries that happen in the laboratory and in the test tube have major potential implications for future treatment and directions of research, however. One of the major obstacles in facilitating discovery from the bench to the bedside rests in the very structures of how research is conducted and funded. The very infrastructures that support science in America are too often the biggest barriers to progress. This is not only a problem for AIDS research, but also a problem for all areas of research on human disease. As we move into the third decade of AIDS, it's critical that the community and the scientific establishment take a hard look at where there is success and where there are failures and find both the will and courage to struggle for meaningful reforms to expedite the process of discovery toward a cure.
Project Inform has written information on a variety of emerging basic science discoveries. To learn more, consider the following reading materials, available through Project Inform's Web site and the hotline:
This article was provided by Project Inform. It is a part of the publication Project Inform Perspective. Visit Project Inform's website to find out more about their activities, publications and services.