MINIREVIEW
The capsid protein of human immunodeficiency
virus: intersubunit interactions during virus assembly
Mauricio G. Mateu
Centro de Biologı
´
a Molecular ‘Severo Ochoa’ (CSIC-UAM), Universidad Auto
´
noma de Madrid, Spain
Introduction
During HIV-1 morphogenesis [1,2], the capsid protein
(CA; or p24) participates in two distinct assembly
events. The first occurs inside the cell and involves the
Gag polyprotein, of which CA constitutes a part. A
spherical capsid comprising up to 5000 Gag subunits is
formed through self-association around a dimer of the
viral RNA genome, which is encapsidated along with
several viral and cellular proteins. Assembly-competent
Gag molecules are bound to the plasma membrane
and may directly interact with molecules of the viral
envelope polyprotein, which are embedded in the
membrane. Thus, condensation of the capsid drives its
coating by an envelope polyprotein-containing lipid
bilayer. As a result of this morphogenetic process, an
immature, non-infectious HIV-1 particle buds from the
infected cell.
Keywords
capsid; conformational stability and
dynamics; human immunodeficiency virus;
molecular recognition; protein association;
protein conformation; protein structure–

merization. The CA–CA interfaces involved in the assembly of the imma-
ture capsid and those forming the mature capsid are different, at least in
part. CA appears to have evolved an extraordinary conformational plastic-
ity, which allows the creation of multiple CA–CA interfaces and the occur-
rence of CA conformational switches. This minireview focuses on recent
structure–function studies of the diverse CA–CA interactions and interfaces
involved in HIV-1 assembly. Those studies are leading to a better under-
standing of molecular recognition events during virus morphogenesis, and
are also relevant for the development of anti-HIV drugs that are able to
interfere with capsid assembly or disassembly.
Abbreviations
CA, capsid protein of HIV-1; cryoEM, cryoelectron microscopy; cryoET, cryoelectron tomography; CTD, C-terminal domain of CA; EM,
electron microscopy; H–D, hydrogen–deuterium; MA, matrix protein; MHR, major homology region; MLV, murine leukemia virus; NC,
nucleocapsid protein; NTD, N-terminal domain of CA; RSV, Rous sarcoma virus.
6098 FEBS Journal 276 (2009) 6098–6109 ª 2009 The Author Journal compilation ª 2009 FEBS
The second capsid assembly event occurs upon bud-
ding of the immature virion. The viral protease-medi-
ated processing of Gag into several independent
proteins and peptides leads to the disassembly of the
spherical capsid inside the virion. Some of the folded
domains of Gag are then able to reassemble as inde-
pendent proteins. The matrix protein (MA; the Gag
N-terminal domain), remains associated with the viral
membrane, forming a discontinuous inner layer. The
nucleocapsid protein (NC) remains associated with the
viral RNA to form the nucleocapsid. In addition, some
1000–1500 subunits out of a larger number of CA mol-
ecules, released as a two-domain protein, self-assemble
into a truncated cone-shaped, hollow structure, namely
the mature HIV-1 capsid. The mature capsid and the

soluble form as a homodimer or homotrimer, its
atomic structure has not been determined. However,
the atomic structures of the separate Gag domains
from HIV-1 (and other retroviruses) have been solved
by X-ray crystallography and ⁄ or NMR spectroscopy.
The N-terminal domain of CA (NTD) and the C-ter-
minal domain of CA (CTD) are small, globular and
mainly helical. NTD contains a-helices 1–7 of CA, and
is connected by a flexible linker to CTD, which
contains a small 3
10
-helix, an extended strand and
a-helices 8–11 of CA (corresponding to helices 1–4 of
CTD) [4–7].
Structural, biochemical and mutational analyses of
the immature HIV-1 capsid have been carried out on
immature virions, or on capsid-like particles that can
be assembled in vitro from full-length or truncated
Gag molecules in the presence of nucleic acid and ⁄ or
other components [8–16]. Electron microscopy (EM) of
negatively stained immature capsid-like particles [8], as
well as cryoelectron microscopy (cryoEM) [14,15] and
cryoelectron tomography (cryoET) [17,18] of immature
capsid-like particles or virions, has revealed a layered
organization, which can be interpreted based on bio-
chemical evidence and the superposition on the elec-
tron density maps of the atomic structure of each
domain. The Gag subunits are radially extended, with
the N-terminal domain, MA, associated with the inner
layer of the viral membrane, and the remaining

face in CA and in the free CTD [6,7]. Mutational
M. G. Mateu Capsid protein interfaces in HIV-1 assembly
FEBS Journal 276 (2009) 6098–6109 ª 2009 The Author Journal compilation ª 2009 FEBS 6099
analyses [23] indicate that this interface could be
involved in the structural organization of the immature
capsid. However, a mutant CTD with a single amino
acid deletion has been recently crystallized as a
domain-swapped dimer [25]. The domain-swapped
interface did not involve helix 9, but instead the major
homology region (MHR), a highly conserved, 20-
amino acid stretch folded as a strand-turn-helix-8
motif. Because of this unusual conservation, numerous
mutational analyses have focused on this stretch, and
have revealed that the MHR is important for many
different steps in the HIV-1 life cycle, including the
assembly of both the mature capsid, where it forms
part of the NTD–CTD interface (see below), and of
the immature capsid [20,23]. Because the MHR also
forms a major part of the domain-swapped dimeriza-
tion interface in the mutant CTD structure, it has been
proposed that this interface could participate in the
assembly of the immature HIV-1 capsid [25]. The
structural and functional studies performed to date
may be not discriminating enough to clearly favor the
involvement of either the domain-swapped or the non-
swapped CTD dimerization interfaces (or both) in the
assembly and stability of the immature HIV-1 capsid.
In summary, in a model [17] of the immature HIV-1
capsid that may be consistent with the experimental
results achieved to date: (a) the capsid lattice is formed

capsids may not be normal precursors of extracellular
HIV-1 virions [26].
Identification of CA–CA interfaces in
the mature HIV-1 capsid
CA multimers with the same structural organization as
authentic mature capsids have been obtained by self-
assembly of CA in vitro, even in the absence of any
other biomolecule, and subjected to structural, bio-
chemical and mutational analyses [27–37]. CryoEM
studies of mature HIV-1 capsid-like particles assembled
in vitro revealed that these are composed of an array of
CA hexamers. Fitting the atomic structures of NTD
and CTD on the cryoEM density map indicated that
NTD connects the CA subunits in each hexamer, and
CTD connects each hexameric ring to six neighbors
through homodimerization [30] (Fig. 1). Similar arrays
of CA hexamers were observed in cryoEM images of
authentic cores isolated from HIV-1 virions [38].
Recently, a CA mutant was used to obtain large,
spherical capsid-like particles that collapsed when
deposited on EM grids. The flattened particles behaved
as 2D CA crystals, and could be used to obtain a
detailed 3D map by electron cryocrystallography [39]
(Fig. 2A). Fitting the atomic structures of NTD and
CTD in this map confirmed and substantially refined
the mature HIV-1 capsid lattice model. Three different
protein–protein interfaces were observed in the CA
Immature Mature
Top
Side

assembled capsids of another retrovirus, Rous sarcoma
virus (RSV), were described [40]. Both capsids are icos-
ahedrally symmetric: one is composed of 12 CA penta-
mers, and the other of 12 pentamers and 20 hexamers.
Pseudoatomic models using the atomic structures of
both CA domains revealed three distinct CA interfaces
similar to those observed within and between hexamers
A
B
C
D
EF
Fig. 2. Structure of CA and the CA hexamer
in the mature HIV-1 capsid [39]. (A) Electron
density map obtained by electron cryocrys-
tallography of the mature HIV-1 capsid lat-
tice; (B, C) Pseudoatomic models of the
CA monomer and hexamer, obtained by
fitting the atomic structures of NTD (green)
and CTD (blue) on the cryocrystallography
electron density map. (C) Showing a top
view of the hexamer, with one monomer
outlined white. (D) View of the hexamer as
in (C), but each CA monomer is depicted in
a different color; (E, F) Mapping on a CA
hexamer (top view and slabbed side view)
of mutations to alanine, according to their
effect on the assembly of mature HIV-1
capsid-like particles: (i) green or blue dots,
mutations in NTD or CTD, respectively, that

the mature HIV-1 capsid has been obtained by X-ray
crystallography of dimeric CTD [6,7]. This interface is
essentially formed by the parallel packing of helix 9
from each monomer, but also involves interactions
between residues in the 3
10
-helix of one monomer and
residues in helices 9 and 10 of the other monomer. No
MHR residues are involved. The structural description
of the dimerization interface in the isolated CTD dimer
is fully consistent with descriptions of the CTD–CTD
interface in the mature HIV-1 capsid. These latter
descriptions derive from: (a) pseudoatomic models of
capsid-like particles [30,39]; (b) analyses of the effect
of CA mutations on the assembly of mature capsid-
like particles (Fig. 2E,F) and ⁄ or the formation of viral
cores; the results obtained showed that residues located
in helix 9 (among others), impaired mature capsid
assembly both in vivo and in vitro [23,34]; and (c)
hydrogen–deuterium (H–D) exchange experiments
analysed by MS. The residues buried in the intersub-
unit interfaces could be identified by their slower H–D
exchange in the assembled particle, relative to the free
CA protein. Again, residues in helix 9 (and others)
were involved in intersubunit interactions [33].
In the atomic structure of CTD, the dimerization
interface involves some 22 amino acid residues from
each monomer, and it would bury approximately
1800 A
˚

tein interfaces, but these generally exhibit affinities
higher than those of CA or CTD (K
d
= 10–20 lm).
In CTD, the dimerization affinity is kept low partly
because several interfacial side chains contribute each
to substantially destabilize the CTD–CTD association
[42]. Quantitative thermodynamic double mutant cycles
clearly showed that a part of this destabilizing effect is
a result of intersubunit electrostatic repulsions at the
CTD–CTD interface, including those between Glu180
from both subunits, that may be conserved in HIV
[36]. It was suggested that such repulsions could arise
as one consequence of a selective pressure to maintain
an optimum balance between capsid stability (i.e. for
structural integrity in the virion) and instability (i.e.
for viral core disintegration and RNA release in the
infected cell) [36].
This thermodynamic description of the CTD
dimerization interface may also apply to the interface
as a part of the HIV-1 capsid: a good correlation
was found between the effects on CTD dimerization
and on capsid-like particle assembly of mutations
that decreased, increased or preserved the affinity, or
showed non-additive effects [6,34,36]. The detailed
structural and thermodynamic descriptions obtained
on the CTD–CTD interface have been already used
in the field of anti-HIV research, for example for the
design of a helix-9 peptide mimic [3,43], and are
Capsid protein interfaces in HIV-1 assembly M. G. Mateu

HIV-1, the high-resolution X-ray model of the modified
CA hexamer from HIV-1, and the pseudoatomic models
of the HIV-1 hexamer obtained from cryo-EM [30] and
electron cryocrystallography [39] maps are all in very
good general agreement regarding the elements forming
the NTD–NTD interface. Helices 1, 2 and 3 of NTD are
closer to the central hole of the hexameric ring, forming
a 18-helix bundle, with helices 1 lining the hole. The
NTD–NTD interface is defined by contacts between
residues in helices 1 and 3 from a NTD monomer and
residues in helices 1 and 2 from the neighboring mono-
mer. These models are also validated by: (a) mutational
analysis, which showed that residues located in helix 1
or 2 impaired mature capsid assembly both in vivo and
in vitro [23,34] (Fig. 2E,F), and (b) H–D exchange
experiments, which identified residues in helices 1 and 2
as involved in intersubunit interactions in mature HIV-1
capsid-like particles [33].
No thermodynamic studies are available on the
NTD–NTD interface. However, in the X-ray structure
of the MLV hexamer, this interface buries a surface
of only 1100 A
˚
2
. Most of the interactions are weak
polar contacts, including some mediated by water
molecules, and a substantial hydrophobic central area
is absent. All these features differentiate the NTD–
NTD interface from the CTD dimerization interface
and many other protein–protein interfaces, and may

a
= +1.1 kcalÆmol
)1
); green, truncation had
no significant effect (DDG
a
< +0.3 to )0.3 kcalÆmol
)1
), or had only a
small negative effect (Lys199; DDG
a
= +0.5 kcalÆmol
)1
); violet,
mutation increased the dimerization affinity (DDG
a
= )0.4 to
)0.8 kcalÆmol
)1
). Figure reproduced with permission [42].
M. G. Mateu Capsid protein interfaces in HIV-1 assembly
FEBS Journal 276 (2009) 6098–6109 ª 2009 The Author Journal compilation ª 2009 FEBS 6103
First, in the pseudoatomic models of capsid-like
particles of the homologous RSV [40], the equivalent
NTD–CTD interface involves the MHR, and previous
genetic analysis revealed that mutations in the MHR
causing a defficiency in assembly were compensated by
secondary mutations that also map in the NTD–CTD
interface [47–49]. Incidentally, one of these mutations
alone eliminated a positive charge from a cluster of

phobic core, and mainly involves polar interactions,
including water-mediated hydrogen bonds and inter-
domain helix-capping interactions.
Finally, the pseudoatomic model of the HIV mature
capsid lattice and mutational analysis [39] (Fig. 2E,F)
are consistent with the above results.
CA–CA interactions and stability of the mature
HIV-1 capsid
Mutations generally located at or close to CA–CA
interfaces, and that either increase or decrease the sta-
bility of mature HIV-1 capsid-like particles [34]
and ⁄ or authentic HIV-1 cores [50], resulted in a loss
of viral infectivity. Thus, the mature HIV-1 cap-
sid ⁄ viral core does appear to have evolved an opti-
mum, delicate balance between stability inside the
virion and instability inside the infected cell. It is
remarkable that different electrostatic repulsions
between neighboring CA subunits through all three
identified interfaces in the mature retrovirus capsid
have been shown or suggested to occur [35,36,40].
Furthermore, covariant mutations during HIV evolu-
tion may have preserved at least a CTD–CTD elec-
trostatic repulsion that was unambiguosly revealed
using a thermodynamic cycle [36]. The low oligomeri-
zation affinity of CA and the stability balance of the
HIV capsid may be a result, in part, of the preserva-
tion of intersubunit electrostatic repulsions.
Conformational rearrangements of CA
and HIV-1 capsid assembly
Both CA domains are covalently connected through a

acting, transient monomers that was thermodynami-
cally characterized. CTD mutant Trp184Ala is unable
Capsid protein interfaces in HIV-1 assembly M. G. Mateu
6104 FEBS Journal 276 (2009) 6098–6109 ª 2009 The Author Journal compilation ª 2009 FEBS
to dimerize [6], even at 1 mm; biophysical and thermo-
dynamic analysis of this monomeric mutant indicated
that it could provide a good structural model for the
transient monomer involved in the dimerization of
nonmutated CTD [41]. Recent NMR studies of this
CTD mutant were consistent with those results, and
revealed that the tertiary structure of the isolated CTD
monomer is not identical to that of the monomeric
subunit in the dimer. In particular, the dimerization
helix 9 is only transiently structured, and the last two
helices are rotated by 90° compared to their position
in dimeric CTD [52].
Subsequently, the structure of another monomeric
CTD mutant, Trp184Ala ⁄ Met185Ala, was reported
[53]. In this structure, helix 9 is shortened but formed,
and the last two helices are placed as in the dimer. It
has been proposed that the structural differences found
for the two monomeric mutants may be a result of the
different pHs used in the NMR experiments [54]. The
structure of the monomer with the transiently formed
helix was determined at neutral pH, whereas that of
the monomer with the structured helix was determined
at acidic pH and, when the pH was raised, the reso-
nances belonging to that helix disappeared [53]. These
pH-dependent changes in tertiary structure are not
unusual in proteins [55,56].

like particles has led to the suggestion that small
conformational changes could also occur in the CTD
dimerization interface, and in the tertiary structure of
CTD itself, during assembly of the mature HIV-1 cap-
sid [39]. The detailed atomic structure and quantitative
thermodynamic description available for the CTD
dimerization interface could be then considered to
define the sterically unconstrained, minimum free
energy conformation. Steric constraints in the mature
HIV-1 capsid lattice could distort and destabilize
somewhat the ‘ideal’ CTD–CTD interface (and per-
haps other CA–CA interfaces). Such constraints could
contribute, in addition to electrostatic repulsions and
other effects, to establish the appropriate balance
between stability and instability of the viral core.
Conformational changes in NTD
During maturation, the proteolytic cleavage of Gag at
the linker between CTD and SP1 could destabilize the
proposed SP1 six-helix bundle, facilitating disassembly
of the immature capsid [17,57]. In addition, processing
of the MA-NTD linker allows the folding as a b-hair-
pin of the NTD N-terminal segment, leading to a local
conformational change in NTD. This rearrangement
has been proposed to destabilize the immature capsid
and ⁄ or create the NTD–NTD interface observed in the
mature HIV-1 capsid, thus promoting core assembly
[58]. In addition, alterations in the H–D exchange pro-
tection pattern when immature and mature virus-like
particles were compared have provided evidence for a
maturation-induced formation of the NTD–CTD inter-

nonmutated CA is able to polymerize into capsid-like
particles [33]. Indeed, there is evidence that, in addition
to conformational changes in CA, physicochemical
conditions having an effect on the chemical activity
(‘effective concentration’) of CA may also play a major
role in the associative properties of NTD and CTD to
form the HIV-1 capsid, as reviewed below.
The concentration of CA inside the mature HIV-1
virion may be at least 3.5 mm [38] (approximately
8mm if an estimation of close to 5000 CA molecules
per virion [16] is accepted). However, in the very lim-
ited space available inside a mature HIV-1 virion,
thousands of molecules of MA, CA, SP1, NC, SP2
and p6, as well hundreds of other viral and cellular
protein molecules and two long RNA molecules, are
found. Thus, in the virion, as in the cell, macromolecu-
lar crowding effects must be in operation as a result of
the exclusion of water molecules from the large frac-
tion of internal volume occupied by the macromole-
cules themselves [61]. The chemical activity, or
‘effective concentration’ of CA in the HIV-1 virion
(upon release from Gag during maturation) must be
not a few millimolar, but much higher. Under these
conditions, protein association reactions, such as CA
assembly, must be strongly favored [61]. The available
experimental evidence summarized below is consistent
with this prediction.
In vitro polymerization of CA into mature HIV-1
capsid-like particles in the virtual absence of macro-
molecular crowding (at maximum protein concentrations

high ionic strength [37]. This reinforces the view that
electrostatic repulsions could contribute to the
observed HIV-1 core instability in infected cells. In
addition, the release of the viral core and many free
CA molecules from the confined space in the virion
into the very large volume within the cell would also
facilitate uncoating by ‘dilution’ (i.e. through a dra-
matic decrease in the CA effective concentration) [50].
These observations indicate that the very high
chemical activity of CA inside the virion as a result of
macromolecular crowding may be critical for the
assembly and stability of the mature HIV-1 capsid.
The very high chemical activity of CA in the maturing
virion may promote association through the CA–CA
interfaces identified, even though both retroviral CA
domains have a low or negligible tendency to oligo-
merize in solution. Similarly (and in addition to con-
densation mediated by MA–plasma membrane and
NC–RNA binding), macromolecular crowding in the
cell may have a strong influence on the assembly of
the immature HIV-1 capsid, by promoting CA–CA
and other weak Gag–Gag interactions.
Acknowledgements
The author acknowledges J. L. Neira for collaboration
and critical reading of the manuscript, and M. del
A
´
lamo, R. Bocanegra and A. Rodrı
´
guez-Huete for

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