Crystal Structure of Key HIV Protein Reveals New Prevention, Treatment Targets

In a finding that unlocks new doors to devising drugs and vaccines against HIV, scientists have crystallized the core of gp120, the surface protein molecule that the virus uses to attach itself to immune system cells.

The new model of the gp120 core’s crystal structure reveals specific targets for anti-HIV vaccines and drugs, and highlights the surprising array of defenses that the virus uses to evade attack.

"Studying the gp120 crystal’s structure can tell us a lot more about how the virus locks on to immune system cells," says Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID). "We now have specific target sites on which to focus in developing new drugs and vaccines."

The research, funded in part by NIAID, comes from a team led by Joseph G. Sodroski, M.D., of the Dana-Farber Cancer Institute, Harvard Medical School, Boston, Mass., and Wayne Hendrickson, Ph.D., of Columbia University College of Physicians and Surgeons, New York, N.Y. Their work appears in the June 18, 1998, issue of Nature and the June 19, 1998, issue of Science.

The scientists confirmed several previously known features but also found some surprises in the crystal structure of the protein. "We discovered that a large part of the gp120 surface is protected against attack by a dense array of carbohydrates and by an amazing capacity to change shape," says Dr. Sodroski.

Among their findings were:

• A shape-shifting device that allows gp120 to shield itself from antibodies until it reaches CD4 receptor sites on the immune system’s T-cells – the first step in hijacking these cells. Loop-shaped projections that stick out above the molecule’s surface hide the critical locking regions. When the virus reaches its target, the loops collapse and move out of the way, unmasking the locking regions.

• An icing of carbohydrate molecules that also shields the receptor-binding regions of the gp120 surface from antibody attacks. Finding a way around these molecules, or even removing them, would be another line of attack against the virus.

• A structure that gp120 uses to attach itself to CCR5, a co-receptor needed to bind CD4 sites on the host cell. Because this structure is stable and therefore vulnerable, it could be another useful target for drugs or vaccines.

• A large "silent face" – a surface that does not react to antibodies and is thus invisible to the immune system.

• A ball-and-socket interaction: a residue of phenylalanine 43 that sticks out from CD4 receptors and fits into a hole on the surface of gp120. This phenylalanine "stick" could be a focus for drugs to block the interaction.

• Several additional cavities in the surface of gp120 that could be exploited to block the molecule from binding to CD4 receptors.

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

The research was funded by NIAID; the National Institute of General Medical Sciences; the Howard Hughes Medical Institute; the American Foundation for AIDS Research; the Aaron Diamond Foundation; the G. Harold and Leila Y. Mathers Foundation; the Friends 10; William McCarty-Cooper; and Douglas and Judi Krupp.

References:

PD Kwong, et al. Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody. Nature 393:648-59 (1998).

R Wyatt, et al. The antigenic structure of the human immunodeficiency virus gp120 envelope glycoprotein. Nature 393:705-11 (1998).

C Rizzuto, et al. A conserved HIV gp120 glycoprotein structure involved in chemokine receptor binding. Science 280:1949-53 (1998).

NIAID is a component of the National Institutes of Health (NIH). NIAID conducts and supports research to prevent, diagnose and treat illnesses such as HIV disease and other sexually transmitted diseases, tuberculosis, malaria, asthma and allergies. NIH is an agency of the U.S. Department of Health and Human Services.

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