|EMBARGOED FOR RELEASE
Wednesday, June 17, 1998
2:00 PM Eastern Time
Crystal Structure of Key HIV Protein Reveals New Treatment Targets
- 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
- Several additional cavities in the surface of gp120 that could be
exploited to block the molecule from binding to CD4 receptors.
The new information on gp120 structure suggests that some current
approaches to AIDS vaccines may not work. For example, vaccines based
on simple gp120 subunits may not get past gp120's ability to hide its
critical binding regions until the last minute. At the same time, the
crystal structure reveals vulnerable parts of gp120's architecture that
researchers could hone in on to devise new drugs and better vaccine
"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.
NIAID supports biomedical research to prevent, diagnose and treat
illnesses such as AIDS, tuberculosis, malaria, asthma and allergies.
NIH is an agency of the U.S. Department of Health and Human Services.
Press releases, fact sheets and other NIAID-related materials are
available via the NIAID Web site at http://www.niaid.nih.gov.
PD Kwong, et al. Structure of an HIV gp120 envelope glycoprotein in
complex with the CD4 receptor and a neutralizing human antibody. Nature
R Wyatt, et al. The antigenic structure of the human immunodeficiency
virus gp120 envelope glycoprotein. Nature 393:648-59 (1998).
C Rizzuto, et al. A conserved HIV gp120 glycoprotein structure involved
in chemokine receptor binding. Science 280:1949-53 (1998).