Viral
Antigens: HIV gp120
David Marcey
© 2006
I.
Introduction
II. Core structure
III. Interactions with receptors
IV. References
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I.
Introduction
Enveloped
viruses use use spike proteins as molecular mimics of host molecules
in order to bind to target cell receptors and gain entry into cells.
However, these spikes serve as convenient antigenic surfaces for immune
system recognition. Mammalian viruses thus face tremendous selective
pressures to change their molecular profiles to evade astoundingly
responsive immune systems capable of recognizing and destroying viral
particles and infected cells. In many cases, natural selection continually
yields viral strains that vary considerably in the antigenic regions
of spike proteins. These genetic variants may arise and spread through
target species periodically, as in the case of annual human flu virus
infections. Or, they may be produced during the course of a single
infection, as in the HIV variants that arise in the large number of
replication cycles that occur over years within a human individual.
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II.
Core Structure
The spike protein of Human Immunodeficiency Virus 1
(HIV-1) responsible for binding to host cell receptor molecules is
glycoprotein 120 (gp120). The
core of this protein is shown at left in a complex with a portion
of a host cell receptor protein (CD4)
and an anti-gp120 antibody Fab fragment
containing heavy and light
chains (Kwong, et al., 1998).
Before looking at the interactions of
gp120 with these
molecules, let's examine the structure of the core gp120
.
The heart-shaped core of
gp120
to your left is oriented pointing downward to the target membrane
(not shown), below. The core comprises 5
alpha helices and 25
beta strands that form numerous beta
sheets.
The beta sheet closest
to the host cell membrane, the bridging sheet,
connects an inner domain on the left
to the outer domain on the right.
There are several loops
that have high sequence variability, permitting the virus to continually
evade immune responses . One of these loops, disordered and therefore
not represented in the crystal structure, lies between residues 396
and 410 (spacefilled).
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III.
Interactions with receptor proteins
The
CD4
receptor is bound
in a groove of gp120 at
the junction of the
bridging
sheet, inner
domain, and outer
domain.
There is not an
exact complementarity of surfaces at the interface of CD4
and gp120. However, upon binding, both
molecules lose significant surface area previously accessible to solvent
(742 Angstroms2 for
CD4,
802 Angstroms2 for
gp120).
CD4
residues in contact with gp120 are mostly
found in a contiguous cluster, whereas gp120
residues involved in binding CD4 are
distributed over several noncontiguous spans, including portions of
the bridging
sheet, inner
domain, and outer
domain.
Crucial interactions are
observed between phe43
of CD4 and
several residues of gp120 that are conserved in all primate
immunodeficiency viruses. These residues are asp368
and glu370 of the outer
domain and
trp427 of the inner
domain. Mutations in these positions block binding
to CD4 (reviewed by Kwong,
et al., 1998).
At
its interface with CD4, gp120
contains numerous surface hydrophobic residues,
a situation that would be thermodynamically unfavorable in a free
protein. This suggests that CD4 binding
induces significant conformational changes in gp120
upon binding.
In addition to binding CD4,
gp120 binding to the surface chemokine
receptor CCR5 is required for HIV infection. The neutralizing antibody
Fab
fragment
shown bound to
gp120 at left overlaps the binding site for CCR5. Humans
carrying variants of CCR5 are resistant to HIV infection, suggesting
that inhibition of CCR5 binding might be an effective way to stop
HIV pathogenesis. gp120 affinity for
CCR5 in vitro is dramatically enhanced by incubation of gp120
with soluble CD4 (Wu, et al.,
1996), demonstrating that the CCR5 binding site on gp120
is formed by conformational changes induced after binding to CD4
(see above).
HIV uses various forms of molecular
trickery to evade immune responses. Most antibodies capable of neutralizing
HIV infection access only the surfaces involved in CD4
or CCR5 binding.
Most of the envelope protein gp120
surface is hidden from circulating antibodies by glycosylation
or by steric exclusion
as gp120
(and gp41) form trimers (Wyatt, et al.,
1998). Conformational changes also provide means for escape. The conformation
of gp120 prior
to binding CD4 may
display side-chain variability, employing the chameleon-like ability
of HIV to change its molecular recognition profile. Also, since the
CD4 binding pocket
is recessed, antibodies may not see this important antigenic feature.
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IV.
References
Kwong, P.D.,
R. Wyatt, J. Robinson, R.W. Sweet, J. Sodroski, W.A. Hendrickson.
Structure of an HIV gp120 envelope glycoprotein in complex with the
CD4 receptor and a neutralizing human antibody. Nature 393,
648-659 (1998).
Wu,
L., N.P. Gerard, R. Wyatt, H. Choe, C. Parolin, N. Ruffing, A. Borsetti,
A.A. Cardoso, E. Desjardin, W. Newman, C. Gerard, J. Sodroski. CD4-induced
interaction of primary HIV-1 gp120 glycoproteins with the chemokine
receptor CCR-5. Nature 384, 179-183 (1996).
Wyatt, R., P.
Kwong, E. Desjardins, R.W. Sweet, J. Robinson, W.A. Hendrickson, J.
Sodroski. The antigenic structure of the HIV gp120 envelope glycoprotein.
Nature 393, 705-711 (1998).
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