HIV hides out in the body like a wolf in sheep's clothing,
covering itself in host cellular debris. Spike-like protein
complexes that lock onto the surface of host cells and
ultimately lead to cellular infection are the only viral
components that protrude beyond this invisibility cloak.
A paper in the February 24 issue of Nature brings
us one giant step closer to penetrating the disguise of
this elusive enemy. The paper describes the physical structure
of one of these spike proteins. This vital information
could ultimately lead to a way of preventing infection
from taking hold.
INDIA
RUBBER PROTEIN
Protein crystallography was used to figure out what
a spike protein called gp120 — derived from the
simian form of AIDS (SIV) — looks like before it
infects host cells. Researchers were amazed at the dramatic
change in gp120's structure before and after cellular
docking.
Apparently, gp120 is the Houdini
of the protein world. It contorts to hide its critical
docking machinery from antibodies until the moment it
locks onto the host cell. Once hooked up with the CD4
receptor, it rearranges itself to deploy other sites
necessary for cellular attachment and infection.
This discovery will help researchers
devise new ways to keep HIV from infecting human cells.
"The structure we have determined enables new thinking
in two directions," explained study author Dr Steven
Harrison, of the Howard Hughes Medical Institute in
Boston. "One direction is, of course, design of new,
small-molecule entry inhibitors. The deep hydrophobic
cavity we have identified has all the hallmarks of a
good drug target."
Researchers knew that the small
molecule BM-378806 inhibited HIV-1 entry into host cells,
but didn't understand how. Now it's apparent that BM-378806
wedges into a deep cavity on gp120's surface, preventing
the protein from locking on to the surface of the host
cell. This discovery should help guide the design of
other small molecules to take advantage of gp120's vulnerabilities.
"The second direction concerns
vaccine development," continued Dr Harrison. "The structure
suggests experiments that may point to strategies for
better immunogen design."
SUGAR
BARRIER
Gaining a better understanding of how the protein is
shaped in its unbound state allows researchers to design
more effective antibodies to neutralize it before it
attacks the host cell. This goal is made more challenging
by gp120's trick of surrounding itself with sugar molecules
that make it difficult for white blood cells to get
a firm grip.
Despite these challenges, understanding
gp120's contortionist ways takes us a step closer to
designing a targeted drug or antibody that could strip
the HIV virus of its disguise, leaving AIDS out in the
cold.
Nature Feb 24, 2005;433:834-41
|
