In a promising advance in the war against AIDS, scientists have designed a potent new protein that can prevent HIV infection by blocking its entry into human cells. The protein, called 5-Helix and designed to bind to a region in the HIV coat protein gp41, is able to prevent a wide range of HIV strains from fusing to the cell membrane and thereby infecting it.
The researchers say that the 5-Helix protein could therefore serve as the basis for a new class of broad-spectrum, injectible drugs against HIV, one that could be used as an alternative when current drugs fail, i.e., as a salvage therapy. Drugs based on 5-Helix would need to be injected, but could be self-administered much the same way as injectible drugs such as insulin or erythropoeitin.
The 5-Helix protein could also serve as a basis for prophylactic drugs that could be injected immediately after inadvertent needle sticks in hospital settings to prevent HIV from infecting cells.
These results, from Professor of Biology Peter S. Kim and colleagues at the Whitehead Institute for Biomedical Research and the Howard Hughes Medical Institute, published in the January 11 issue of ScienceExpress (an electronic publication of Science magazine highlighting papers from future issues), hold great promise for clinical applications.
The American public may have become complacent about the HIV epidemic largely due to the success of the triple-cocktail drug therapies. However, HIV continues to be a major public health menace worldwide, infecting more than 33 million people. While developed countries have access to the expensive drugs that suppress HIV infection, many poorer countries with large, infected populations have no treatment options. Even more alarming, the wily virus is mutating to form variants, which escape treatment by the existing drugs.
"Current therapy is working, but sexual transmission of virus that is resistant to treatment has been documented, making it important to continue to find new targets and therapies for stopping HIV," Professor Kim said.
Unlike currently used drugs that target HIV at other points during its life cycle&emdash;after it has already infected the cell -- drugs based on 5-Helix could work by preventing HIV fusion with cell membranes. Such "entry inhibitors" represent a promising and alternative line of attack against HIV. In fact, one entry inhibitor, called T-20, has shown promise in Phase II clinical trials when injected into patients, but it must be injected in large quantities.
The 5-Helix protein is a potent, broad-spectrum inhibitor of HIV infection that targets a different part of the HIV coat protein than T-20. The researchers are particularly excited by the results they see in the 5-Helix protein. "We may only be a few steps away from seeing whether 5-Helix works in monkeys," Professor Kim said.
This report is the culmination of decades-long research into the structure of the HIV coat protein, gp41. Two years ago, Professor Kim's Whitehead lab used X-ray crystallography to decipher the architecture of gp41. This protein plays a key role in allowing the virus membrane to fuse with the membrane of the cell it is attacking. Scientists have long targeted gp41, hoping that a drug aimed at this protein could nip HIV infection in the bud by blocking the virus's ability to enter cells.
In its inactive form, gp41 lies just beneath the surface of the virus coat, but as HIV prepares to enter a cell, gp41 undergoes a remarkable change. A dormant protein region called the "fusion peptide" is propelled, harpoon-like, toward the host cell membrane, hooking the target for infection. For a fleeting moment, the exposed gp41 is an Achilles' heel for the virus -- vulnerable to counterattack by drugs.
The Kim lab designed 5-Helix to bind specifically and tightly to a portion of gp41. Even at minute concentrations, the 5-Helix was able to prevent HIV from entering cells.
5-Helix also has other qualities that make an attractive drug candidate. It is very stable, so it is less likely to be degraded by the body's enzymes; it can be made larger to avoid elimination by the kidneys; and it can be modified such that it can escape the body's immune response.
The 5-Helix strategy may have broader application to a wide range of human viruses. Like HIV, many different viruses -- including Ebola, HRSV (human respiratory syncytial virus, a leading cause of infant mortality in developed countries), and the flu virus -- use a similar fusion membrane strategy to enter cells. The 5-Helix protein can be used as a model to design similar inhibitors against HRSV, for instance.
The 5-Helix results also suggest a new strategy for generating antibodies against HIV, which may be useful in vaccine development.
NEXT STEP
Now that the researchers know that 5-Helix is a potent inhibitor of HIV in cell culture against a wide variety of HIV isolates, the next step is to find out whether or not it has antiviral activity in an animal model. "If 5-Helix-like molecules did work in animals, then the difficult and arduous process of developing it for humans could begin to take place," Professor Kim said.
A version of this article appeared in MIT Tech Talk on January 24, 2001.
