United Press International; Wednesday June 17 5:46 PM EDT
Lidia Wasowicz, UPI Science Writer

The unmasking of how the elusive human immunodeficiency virus, HIV, which causes acquired immune deficiency syndrome, AIDS, unlocks and enters unsuspecting cells could prove the undoing of the perpetrator of death and destruction _ although it's still too early to tell for certain, they say.

In four studies published in two journals, the investigators report obtaining the first detailed, three-dimensional picture of the lock-and- key mechanism by which HIV latches onto blood cells. They view the feat as a milestone along the obstacle-riddled path toward developing vaccines that are effective against the numerous strains of HIV.

"This work provides an important foundation for researchers working on new AIDS drugs and vaccines," says Dr. Joseph Sodroski of the Dana- Farber Cancer Institute in Boston, a team leader who co-authored studies that will appear in Thursday's issue of Nature and in Friday's issue of Science.

"HIV is a viral Houdini. It carries a heavily protected infection machinery that frustrates host defenses. Understanding this machinery should help us target medical interventions to the weak spots in the armor."

While the researchers caution against a rush to judgment, noting that it is too early to tell whether such an approach will live up to their expectations or how soon it could actually lead to improved drugs and vaccines, they nevertheless admit they are hard-pressed to suppress their excitement.

"We now have specific target sites on which to focus in developing new drugs and vaccines," says Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases in Bethesda, Md., and one of the country's leading AIDS experts.

"The crystal structure tells us how the virus is able to bind to the receptor at the same time that it remains sufficiently changeable to avoid immune detection. There is the potential for the information to be used to design compounds that interfere and block that interaction," says the other team leader, Wayne Hendrickson of the Howard Hughes Medical Institute and Columbia University in New York.

Peter Kwong, associate research scientist at Columbia and lead author of one of the Nature papers, adds, "Knowing the structure down to the atomic details will provide valuable clues for vaccine design."

The hope springs from the researchers' success in determining the precise structure of a protein on the surface of HIV-1. The virus uses this protein, called gp120, to attach itself to immune system cells, opening the way to infection and, ultimately, AIDS.

Knowing the specifics of this interlocking mechanism can disclose critical information about how the virus evades attack from the immune system, Hendrickson says.

The new model of the crystal structure of gp120's core unveils specific targets for vaccines and drugs and showcases a surprising array of defenses the virus uses to outsmart the forces of the body's disease- fighting system.

The four papers focus on how gp120 links up with two proteins _ CD4 and chemokine receptors _ on the surface of immune system cells.

To succeed where many others in the 10-year worldwide effort to chart gp120's three-dimensional structure had failed, Sodroski and Hendrickson used X-ray crystallography. This technique passes X-rays through a crystal from many angles, determines their pattern of diffraction, and assembles the data to reveal the protein's every component _ right down to individual atoms.

Removing the protein's cloak of secrecy has been so long in coming because the unusual flexibility of HIV-1's coat, or envelope, and its penchant for disguise have thwarted researchers' efforts at every turn.

"The envelope has many flexible loops and sugars that do not easily lend themselves to a rigid crystalline structure," Sodroski says. "Creating a crystal of the envelope is like trying to build a house with many different-sized bricks."

Sodroski and Hendrickson overcame the odds by trimming the sugars and the flexible, outlying regions and concentrating on the common core sections found in all HIV strains.

Being able to focus on the common portions of the viral protein coat may lead to vaccines that work against more than one strain, says co- researcher Richard Wyatt of Columbia.

The mapping of gp120 may revitalize efforts to create vaccines based on the immune system recognizing a portion of the protein. In one such trial, which ended in 1996, patients inoculated with a gp120-based vaccine fared no better than those who got a placebo.

Earlier this month, the Food and Drug Administration gave its green light to a Phase III test of another variation on the same theme. Future experiments could target other portions of the molecules shown in the new research to play a key role in infection.

The crystal structure also reveals potential new drug targets.

"At the interface of the gp120/CD4 receptor is a large cavity that is a drug designer's dream. The deep cavity at the heart of the interaction is just begging to be filled with a high-affinity inhibitor, " Kwong says.

Concludes Sodroski, "This first structure will provide a foundation for people to look at this protein as the basis of a vaccine and modify it to optimize it. It will stimulate a lot of new work."

980617
UP980603

Always watch for outdated information. This article first appeared in 1998. This material is designed to support, not replace, the relationship that exists between you and your doctor.

AEGiS presents published material, reprinted with permission and neither endorses nor opposes any material. All information contained on this website, including information relating to health conditions, products, and treatments, is for informational purposes only. It is often presented in summary or aggregate form. It is not meant to be a substitute for the advice provided by your own physician or other medical professionals. Always discuss treatment options with a doctor who specializes in treating HIV.

Copyright ©1980, 1998. AEGiS. All materials appearing on AEGiS are protected by copyright as a collective work or compilation under U.S. copyright and other laws and are the property of AEGiS, or the party credited as the provider of the content. .