Understanding HIV:
Lipid rafts

April 2004     View PDF     En español

Over the past twenty years, a wealth of discoveries has been made in HIV research, perhaps unparalleled in the history of biomedical research. Since the early days of the epidemic, scientists’ understanding of HIV and the immune system has advanced leaps and bounds. Yet, the fruits of very basic scientific research rarely appear immediately.

Certainly the scientific process is far from ideal in turning information that’s learned in the lab into advances in therapy and patient care. Still, advances in basic science have greatly improved the care of people living with HIV. This publication sheds light on a new emerging theory about the role and implications of cholesterol in HIV infection.

Adhesion molecules on cells bind or adhere to various particles found in the blood. They help transport material across the cell membrane and into the cell. It has been shown that all major adhesion molecules interact with HIV. When these molecules are present on the cell surface, the quantities of HIV binding to a cell increases from a few hundred to thousands. These molecules not only increase HIV’s ability to bind to the cell, but they also increase its ability to infect the cell and help transport the virus into it. Moreover, when HIV is bound to one of these molecules, it’s much more difficult for the immune system to target and neutralize or eliminate it.

In addition to how adhesion molecules help HIV to bind and infect cells, they also play a key role in allowing infected cells to release new HIV. HIV has to get into the cell in order to use it to reproduce, but it also has to get back out.

 

THE ROLE OF LIPID RAFTS

CD4+ cell surface and lipid raft
found next to CD4+ receptor

 

Lipid raft moving
towards co-receptor

 

After binding, lipid raft moves
HIV to co-receptor

 

HIV moves into CD4+ cell

 

Work by Dr. James Hildreth of Johns Hopkins University, and others, has 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 several functions that include transporting materials into, out of and throughout cells. They’re not only important for HIV, but for other viruses such as influenza and measles (which also bind to and bud from them). Understanding the role of lipid rafts in HIV may have important implications for developing new therapies.

Cholesterol is found in all tissues, oils, fats, blood, etc. It is a key component of lipid rafts. Hildreth and his team conducted experiments to identify the role of cholesterol and lipid rafts in HIV infection. Using a compound called beta-cyclodextrin (BCD), Hildreth was able to change the cholesterol level in cells. This eliminated about 90% of the cholesterol within one hour. Hildreth’s team discovered the following:

• Removing cholesterol from cells with BCD make the cell resistant to HIV infection.
• Cholesterol-depleted cells release non-infectious HIV particles. (The cells that are cholesterol-depleted produce less than 5% of infectious HIV compared to cells that are not cholesterol-depleted.) When these cells are given back cholesterol, they again produce infectious HIV.
• Importantly, Hildreth’s team used BCD to deplete cholesterol from HIV itself. When HIV was depleted of cholesterol, it became inactive and non-infectious. When the virus was given back cholesterol, it became infectious again.

Hildreth’s work underscores the importance of lipid rafts and cholesterol in HIV infection and its budding from cells. Hildreth concludes that intact lipid rafts and cholesterol are required for HIV to be infectious.

Hildreth’s team wants to apply these discoveries to inventing a topical microbicide that might be used to prevent HIV infection. (Topical microbicides are usually creams or gels that could be used as a vaginal and/or anal suppository, perhaps even added to lubricant.) The goal is to identify a compound with anti-HIV activity that could disable HIV and prevent its transmission through sex. The Johns Hopkins group has been exploring using beta-cyclodextrin as an HIV microbicide.

Unlike nonoxynol-9, a much studied topical microbicide, BCD is not toxic to cells, particularly those in the vaginal tract, called epithelial cells. Animal studies suggest that nonoxynol-9 completely destroys epithelial cells, which are important to protect women from infections that can cause gynecologic complications. However, BCD showed minimal toxicity to epithelial cells. It also greatly inhibited the transmission of HIV, whether the BCD was simply used to treat vaginal cells or if it was used intravaginally.

While cholesterol-depleting approaches may have important implications for HIV prevention and microbicides, there are also implications for treatment that have yet to be fully explored and need investigation. Dr. Eric Freed of the National Institutes of Health has also conducted lab studies of BCD and shows that its anti-HIV activity is dependent on its dose (the higher the dose, the greater HIV is inhibited). His research also confirms that BCD is not causing overall toxicity to cells. Dr. Freed has examined a common cholesterol-lowering agent, a statin inhibitor called simvastatin (Zocor). His work suggests that simvastatin can decrease HIV replication, which raises the opportunity to explore whether they’re useful as anti-HIV drugs.

Basic science discoveries about the immune system and HIV can often seem removed from the real world of people living with HIV. However, discoveries that happen in the lab have major potential implications for future treatment and directions of research. One of the major obstacles in helping this discovery move from the lab to the bedside rests in the very systems of how research is conducted and funded.

The 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 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.