intriguing interplay between viral proteins during herpesvirus assembly or: the herpesvirus assembly...
TRANSCRIPT
Intriguing interplay between viral proteins during herpesvirus
assembly or: The herpesvirus assembly puzzle
Thomas C. Mettenleiter *
Institute of Molecular Biology, Friedrich-Loeffler-Institut, Insel Riems, Germany
Abstract
Herpes virions are complex particles that consist of more than 30 different virally encoded proteins. The molecular basis of
how this complicated structure is assembled is only recently beginning to emerge. After replication in the host cell nucleus viral
DNA is incorporated into preformed capsids which leave the nucleus by budding at the inner nuclear membrane resulting in the
formation of primary enveloped virions in the perinuclear space. The primary envelope then fuses with the outer leaflet of the
nuclear membrane, thereby releasing nucleocapsids into the cytoplasm. Final envelopment including the acquisition of more
than 15 tegument and more than 10 envelope (glyco)proteins occurs by budding into Golgi-derived vesicles. Mature virions are
released after fusion of the vesicle membrane with the plasma membrane of the cell. Thus, herpesvirus morphogenesis requires a
sequence of envelopment–deenvelopment–reenvelopment processes which are distinct not only in the subcellular compartments
in which they occur but also in the viral proteins involved. This review summarizes recent advances in our understanding of the
complex protein–protein interactions involved in herpesvirus assembly and egress.
# 2005 Elsevier B.V. All rights reserved.
Keywords: Herpesvirus; Morphogenesis; Tegument proteins; Glycoproteins
www.elsevier.com/locate/vetmic
Veterinary Microbiology 113 (2006) 163–169
1. Introduction
Herpes virions consist of more than 30 virally
encoded proteins which are present in four morpho-
logically distinct components (Roizman and Knipe,
2001). The inner core contains the viral genomic
double-stranded DNA which is enclosed in an
icosahedral (T = 16) capsid. The nucleocapsid is
surrounded by a proteinaceous tegument of more than
15 different viral proteins, which, like the matrix in
RNA viruses, links the envelope with the nucleocapsid.
* Tel.: +49 383 517 250; fax: +49 383 517 151.
E-mail address: [email protected].
0378-1135/$ – see front matter # 2005 Elsevier B.V. All rights reserved
doi:10.1016/j.vetmic.2005.11.040
Within the virion envelope ca. 10 or more virally
encoded (glyco)proteins are inserted which fulfill
important functions in particular during virus entry in
the initial stages of infection. All these different
proteins have to be correctly assembled during virion
morphogenesis to form a mature infectious virus
particle (Steven and Spear, 1997).
Envelope glycoproteins are important for mediat-
ing the interaction of extracellular virions with their
cognate cellular receptors (Spear and Longnecker,
2003) as well as for fusion between the virion
envelope and the plasma membrane (Spear, 1993)
which is still considered the prototypic mode of
herpesvirus infection although in several virus-cell
.
T.C. Mettenleiter / Veterinary Microbiology 113 (2006) 163–169164
systems endocytosis has been proposed to be involved
in infectious entry of herpesviruses (Gianni et al.,
2004, Nicola and Straus, 2004).
After fusion of viral and cellular membranes the
majority of tegument proteins dissociates from the
incoming nucleocapsid and, at least part of them, prime
the cell for synthesis of viral components. Thus, the
UL48 protein of alphaherpesviruses transactivates viral
immediate-early gene expression (Batterson and Roiz-
man, 1983), whereas the UL41 protein is involved in
degradation of mRNAs to effect the virus-induced host
cell shutoff (Kwong and Frenkel, 1989). However, not
all tegument proteins are detached from the capsid
during entry, and it has recently been demonstrated that
at least the components of the capsid-proximal
tegument which contains the UL36, UL37 and US3
gene products remain associated with the capsid until it
docks at the nuclear pore (Granzow et al., 2005).
After viral gene expression and DNA synthesis,
capsid proteins are translocated from the cytoplasm to
the nucleus where they assemble autocatalytically into
preformed capsids which then package DNA in a
process that resembles head assembly and DNA
packaging in bacteriophages (Baines and Weller,
2005). Genome containing capsids acquire an envelope
by budding at the inner nuclear membrane in a process
that has been designated as primary envelopment. By
fusion of the primary envelope with the outer nuclear
membrane, designated as deenvelopment, capsids are
translocated into the cytoplasm where they gain their
final tegument and envelope by a secondary envelop-
ment process. Thus, the herpesvirus replication cycle is
characterized by two distinct budding and fusion
processes, which occur in different subcellular com-
partments and are also differentiated by the viral
proteins involved (for comprehensive recent reviews
see Mettenleiter, 2002; Mettenleiter, 2004).
2. Primary envelopment
For primary envelopment, viral proteins homolo-
gous to the products of the HSV-1 genes UL31 and
UL34 are required. UL34 encodes a type II transmem-
brane protein which physically interacts with the UL31
gene product (Fuchs et al., 2002a, Lake and Hutt-
Fletcher, 2004; Reynolds et al., 2002; Sanchez and
Spector, 2002). Coexpression of UL31 and UL34 is
required for proper positioning of both proteins at the
inner nuclear membrane, which, in turn, is required for
primary envelopment. Moreover, coexpression of
UL31 and UL34 alters lamin architecture (Reynolds
et al., 2004; Simpson-Holley et al., 2004) and it has been
shown that UL34 is able to interact with cellular protein
kinase C recruiting this protein for phosphorylation and
subsequent partial dissolution of the nuclear lamina
(Muranyi et al., 2002), a prerequisite for intranuclear
capsids to gain access to the envelopment site.
However, how intranuclear capsids are directed towards
the budding site is still unclear. It is interesting that
UL31 and UL34 homologs are found throughout the
three herpesvirus subfamilies which indicates that
primary envelopment is a basic, conserved process in
herpesvirus replication. The UL34 protein likely
represents a component of the primary envelope,
whereas the UL31 protein is thought to be part of the
primary tegument. In the absence of the UL31 and
UL34 proteins, intranuclear capsids do not access the
inner nuclear membrane for primary envelopment. So
far, no mutant virus has been described which is
blocked specifically at primary envelopment, i.e. no
mutations that result in accumulation of intranuclear
capsids lining the inner nuclear membrane have been
described. Primary enveloped virus particles apparently
differ from mature virions morphologically (Granzow
et al., 2001) and by their biochemical composition
(Granzow et al., 2004). Whereas the UL31 and UL34
proteins are part of primary virions, they are absent
from mature virus particles (Fuchs et al., 2002a). This
demonstrates that they are lost during further morpho-
genesis steps. In contrast, major components of the
tegument of mature virions are absent from primary
enveloped particles (Granzow et al., 2003). So far, in the
alphaherpesviruses the only protein that has unequi-
vocally been demonstrated to be part of the tegument of
both forms of enveloped virions is the US3 protein
kinase (Granzow et al. 2004; Reynolds et al., 2002).
Interestingly, this protein plays a role in deenve-
lopment, i.e. fusion of the primary envelope with the
outer nuclear membrane. This process occurs in the
absence of glycoproteins, which are essential for
fusion during entry, e.g. gB or gH indicating that it is
fundamentally different from the fusion event result-
ing in initiation of infection. In the absence of the US3
protein, deenvelopment is impaired and primary
enveloped virions accumulate in the perinuclear space
T.C. Mettenleiter / Veterinary Microbiology 113 (2006) 163–169 165
(Klupp et al., 2001a; Reynolds et al., 2002), which
makes this mutant a good tool to ultrastructurally
analyze these primary virions. How US3 influences
deenvelopment is unclear, but this effect appears to be
correlated with its kinase activity (Reynolds et al.,
2002). Whereas it had previously been postulated that
the effect is due to phosphorylation of the UL34
protein by US3 (Purves et al., 1992), this is probably
not the case (Klupp et al., 2001a, 2001b; Ryckman and
Roller, 2004).
It is interesting to note that primary envelopment
apparently depends to a large extent on the presence of
DNA-containing nucleocapsids. Envelopment of empty
or scaffold-protein containing capsids is only rarely
observed as is envelopment of primary tegument
without involvement of capsids (‘primary L-particles’;
Granzow et al., 1997; Aleman et al., 2003).
3. Secondary envelopment
After fusion of the primary envelope with the outer
nuclear membrane, nucleocapsids are released into the
cytoplasm. Although they appear ‘naked’ by conven-
tional electron microscopy, immunolabeling studies
indicated that they carry the US3, UL36 and UL37
proteins (Fuchs et al., 2002b). Whether these proteins
are in fact added during primary envelopment and
remain associated with the translocated capsid, or
whether they are recruited early after nuclear egress is
unclear. As mentioned above, immunolabeling studies
did not indicate presence of UL36 or UL37 proteins in
primary PrV virions, whereas the US3 protein is
present in primary enveloped HSV-1 or PrV particles.
Tegumentation in the cytoplasm and secondary
envelopment by budding into trans-Golgi vesicles are
dependent on a complex network of protein–protein
interactions, which has only recently been started to be
unraveled. The inner tegument is presumably formed
by the largest protein expressed in the herpesvirus
family, the product of the conserved UL36 gene. The
UL36 homologous proteins are between ca. 2000 and
3500 amino acids in size. This protein presumably
contacts the capsid (Chen et al., 1999; Zhou et al.,
1999) and it has been shown to bind the UL37 protein
(Klupp et al., 2001b, 2002; Fuchs et al., 2004), which
may therefore represent a second layer of tegument.
Located in the capsid-associated tegument is also
the US3 protein (Granzow et al., 2004). How
(partially) tegumented capsids are directed to the site
of secondary envelopment is unclear. However, at the
secondary envelopment site, i.e. at vesicles of the
trans-Golgi, other tegument proteins assemble which
include the UL11 and UL49 proteins. In PrV, the latter
has been shown to interact with the carboxyterminal,
intracytoplasmic domains of glycoproteins gE and gM
(Fuchs et al., 2002c). This interaction is required for
the inclusion of the UL49 protein into mature virions.
Deletion of gM alone impairs secondary envelopment
to some extent, whereas absence of gE alone has no
effect. Simultaneous absence of gE, or the cytoplasmic
tail of gE, and gM drastically impairs virion formation
and rather large clusters of capsids embedded in
tegument accumulate in the cytoplasm (Brack et al.,
1999, 2000). Apparently, in the absence of these
glycoproteins, capsids still acquire tegument but are
unable to contact the envelopment site. A similar
phenotype was observed in HSV-1 mutants simulta-
neously lacking gE and gD (Farnsworth et al., 2003),
whereas a gE and gM deletion mutant of HSV-1 was
not significantly impaired (Browne et al., 2004). This
could indicate that requirements for secondary
envelopment are different even within herpesvirus
subfamilies (Spengler et al., 2001). In PrV, absence of
gM and the membrane-associated tegument protein
UL11 yielded the most drastic phenotype with huge
intracytoplasmic accumulations of capsids embedded
in tegument (Kopp et al., 2004). Since gM has been
shown to retain envelope proteins in the Golgi area
(Crump et al., 2004) and UL11 has been demonstrated
to have Golgi-targeting properties (Bowzard et al.,
2000), it is hypothesized that in the simultaneous
absence of both neither the gathering of glycoproteins
at the future budding site nor the targeting of tegument
proteins to this site occurs resulting in an abolishment
of secondary envelopment. It is interesting to note that
UL11 and gM are conserved in the herpesvirus family,
whereas gE and UL49 are not. Recently, the UL49
protein of HSV-1 has been proposed to also bind to the
cytoplasmic tail of gD (Chi et al., 2005). However, the
HSV-1 UL49 might also have an intrinsic ability to
bind to membranes in the absence of other viral
proteins (Brignati et al., 2003).
Studies from HSV-1 and PrV also indicate a
prominent role for the alphaherpesvirus UL48 protein
in virion maturation. In the absence of this tegument
T.C. Mettenleiter / Veterinary Microbiology 113 (2006) 163–169166
component, secondary envelopment is strongly inhib-
ited (Mossman et al., 2000; Fuchs et al., 2002b) and
nucleocapsids accumulate dispersed in the cytoplasm
(Fuchs et al., 2002b). This accumulation is strikingly
different from those found in the absence of envelope
proteins (capsids embedded in tegument; see above) or
in the absence of the UL37 inner tegument protein
(capsids in regular, hexagonal order; Klupp et al.,
2001a,b). Thus, the UL48 protein could be the adaptor
that links membrane-associated tegument like UL49
and UL11 with capsid-associated tegument proteins
such as UL36 and UL37. However, so far no direct
interaction between the UL48 protein and either the
capsid or capsid-associated tegument proteins has
been found. In contrast, physical interactions between
UL48 and UL49, UL48 and UL41, and functional
interactions between the UL46, UL47 and UL48
proteins have been described (reviewed in Mettenlei-
ter, 2002). In the varicellovirus bovine herpesvirus 1
(BHV-1), the UL3.5 protein, which is not present in
HSV-1, interacts with the UL48 protein (Lam and
Letchworth, 2000), and absence of the UL3.5 protein
from PrV impairs virion formation to a similar extent
Fig. 1. Diagram of molecular interactions during virion formation of HSV-1
deenvelopment (2), and secondary envelopment (3). Solid lines or direct
products indicate physical interaction, whereas arrows indicate functiona
interactions. Between glycoproteins, only direct contacts resulting in the for
three herpesvirus subfamilies are marked in red. The UL3.5 protein (blue)
modified and updated from Mettenleiter, 2002, 2004 with permission from
(For interpretation of the references to color in this figure legend, the rea
as absence of UL48. Thus, the UL3.5-UL48 complex
may in fact be the functional unit in BHV-1 and PrV. In
HSV-1, the UL48 protein has been shown to bind to
the cytoplasmic tail of gH (Gross et al., 2003).
Other components of the tegument are even less
well understood. The conserved UL11, UL16 and
UL21 proteins may form a tripartite complex (Loomis
et al., 2003; Klupp et al., 2005) but its role in virion
formation is unclear. The UL20 protein, which is
present only in alphaherpesviruses, has been described
to be involved in virion maturation (Avitabile et al.,
1994; Fuchs et al., 1997), presumably by its
interaction with envelope glycoprotein K which
depends on UL20 for proper processing (Dietz
et al., 2000; Foster et al., 2003).
In particular in situations in which tegumentation
of cytoplasmic nucleocapsids is impaired, L-particles
are formed in abundance (McLauchlan and Rixon,
1992. They consist of enveloped tegument proteins
indicating that secondary envelopment is not depen-
dent on the presence of nucleocapsids. Although the
exact composition of L-particles is still not clear, they
contain virion envelope and tegument proteins.
and/or PrV. Numbers in triangles indicate primary envelopment (1),
contacts between the rectangles representing the designated gene
l effects. Dotted lines denote suggested but not firmly established
mation of physical complexes are depicted. Proteins conserved in all
is absent from HSV-1, but present in PrV and BHV-1 virions (figure
the American Society for Microbiology and Elsevier Publications).
der is referred to the web version of this article).
T.C. Mettenleiter / Veterinary Microbiology 113 (2006) 163–169 167
A specific blockage of envelopment such as in the
absence of the gE and gM (Brack et al., 1999) or UL11
and gM proteins of PrV (Kopp et al., 2004) also blocks
the formation of L-particles indicating that an
interaction between membrane proteins and tegument
proteins as seen in secondary envelopment of nucle-
ocapsids has to occur.
In Fig. 1, the hitherto known interactions between
viral structural components primarily of PrVand HSV-
1 are graphically depicted. Although this network of
interactions is already rather complex, it is still far
from finalized. Several tegument proteins have yet to
be fitted in and different complexes have to be joined
to finally end up in a mature herpesvirus particle.
In summary, herpesviruses have evolved an
elaborate pathway for egress from the host cell and
for assembly of a highly complex virus particle. Two
envelopment processes occur in different subcellular
compartments involving different viral proteins. This
may reflect the evolution of the herpesviruses. In many
molecular parameters, herpesviruses resemble dsDNA
bacteriophages which indicates that both may have a
common origin. It is therefore possible that ancestors
of herpesviruses had infected prokaryotes which
evolved into the eukaryotic cell nucleus, and that
they left their previous hosts using the primary
envelopment mechanism with the need to acquire a
second envelopment system after the original host
became an endosymbiont.
Acknowledgments
Work in my laboratory is supported by the
Deutsche Forschungsgemeinschaft. I thank all co-
workers for their assistance and ongoing support.
References
Aleman, N., Quiroga, M., Lopez-Pena, M., Vazquez, S., Guerriero,
F., Nieto, J., 2003. L-particle production during primary replica-
tion of pseudorabies virus in the nasal mucosa of swine. J. Virol.
77, 5657–5667.
Avitabile, E., Ward, P., di Lazzaro, C., Torrisi, M., Roizman, B.,
Campadelli-Fiume, G., 1994. The herpes simplex virus UL20
protein compensates for the differential disruption of exocy-
tosis of virions and viral membrane glycoproteins associated
with fragmentation of the Golgi apparatus. J. Virol. 68, 7397–
7405.
Baines, J.D., Weller, S.K., 2005. Cleavage and packaging of herpes
simplex virus 1 DNA. In: Catalano, C.E. (Ed.), Viral Genome
Packaging Machines: Genetics, Structures, and Mechanism,
Landes Biosciences, Georgetown, TX, USA.
Batterson, W., Roizman, B., 1983. Characterization of the herpes
simplex virion-associated factor responsible for the induction of
a genes. J. Virol. 46, 371–377.
Bowzard, J.B., Visalli, R.J., Wilson, C.B., Loomis, J.S., Callhan,
E.M., Courtney, R.J., Wills, J.W., 2000. Membrane targeting
properties of a herpesvirus tegument protein-retrovirus Gag
chimera. J. Virol. 74, 8692–8699.
Brack, A.R., Klupp, B.G., Granzow, H., Tirabassi, R., Enquist, L.W.,
Mettenleiter, T.C., 2000. Role of the cytoplasmic tail of pseu-
dorabies virus glycoprotein E in virion formation. J. Virol. 74,
4004–4016.
Brack, A.R., Dijkstra, J., Granzow, H., Klupp, B.G., Mettenleiter,
T.C., 1999. Inhibition of virion maturation by simultaneous
deletion of glycoproteins E, I, and M of pseudorabies virus.
J. Virol. 73, 5364–5372.
Brignati, M.J., Loomis, J.S., Wills, J.W., Courtney, R.J., 2003.
Membrane association of VP22, a herpes simplex virus type
1 tegument protein. J. Virol. 77, 4888–4898.
Browne, H.M., Bell, S., Minson, T., 2004. Analysis of the require-
ment for glycoprotein M in herpes simplex virus type 1 mor-
phogenesis. J. Virol. 78, 1039–1041.
Chen, D., Jiang, H., Lee, M., Liu, F., Zhou, Z.H., 1999. Three-
dimensional visualization of tegument/capsid interactions in the
intact human cytomegalovirus. Virology 260, 10–16.
Chi, J., Harley, C.A., Mukhopadhyay, A., Wilson, D.W., 2005. The
cytoplasmic tail of herpes simplex virus envelope glycoprotein
D binds to the tegument protein VP22 and to capsids. J. Gen.
Virol. 86, 253–261.
Crump, C., Bruun, B., Bell, S., Pomeranz, L.E., Minson, T., Browne,
H.M., 2004. Alphaherpesvirus glycoprotein M causese the
relocalization of plasma membrane proteins. J. Gen. Virol.
85, 3517–3527.
Dietz, P., Klupp, B.G., Fuchs, W., Kollner, B., Weiland, E., Met-
tenleiter, T.C., 2000. Pseudorabies virus glycoprotein K requires
the UL20 gene product for processing. J. Virol. 74, 5083–5090.
Farnsworth, A., Goldsmith, K., Johnson, D.C., 2003. Herpes sim-
plex virus glycoproteins gD and gE/gI serve essential but
redundant functions during acquisition of the virion envelope
in the cytoplasm. J. Virol. 77, 8481–8494.
Foster, T.P., Alvarez, X., Kousoulas, K.G., 2003. Plasma membrane
topology of syncytial domains of herpes simplex virus type 1
glycoprotein K (gK): the UL20 protein enables cell surface
localization of gK but not gK-mediated cell–cell fusion. J. Virol.
77, 499–510.
Fuchs, W., Klupp, B.G., Granzow, H., Mettenleiter, T.C., 1997. The
UL20 gene product of pseudorabies virus functions in virus
egress. J. Virol. 71, 5639–5646.
Fuchs, W., Klupp, B.G., Granzow, H., Mettenleiter, T.C., 2004.
Essential function of the pseudorabies virus UL36 gene product
is independent of its interaction with the UL37 protein. J. Virol.
78, 11879–11889.
T.C. Mettenleiter / Veterinary Microbiology 113 (2006) 163–169168
Fuchs, W., Klupp, B.G., Granzow, H., Hengartner, C., Brack, A.,
Mundt, A., Enquist, L.W., Mettenleiter, T.C., 2002c. Physical
interaction between envelope glycoproteins E and M of pseu-
dorabies virus and the major tegument protein UL49. J. Virol.
76, 8208–8217.
Fuchs, W., Klupp, B.G., Granzow, H., Osterrieder, N., Metten-
leiter, T.C., 2002a. The interacting UL31 and UL34 gene
products of pseudorabies virus are involved in egress from
the host-cell nucleus and represent component of primary
enveloped but not of mature virions. J. Virol. 76, 364–
378.
Fuchs, W., Granzow, H., Klupp, B.G., Kopp, M., Mettenleiter, T.C.,
2002b. The UL48 tegument protein of pseudorabies virus is
critical for intracytoplasmic assembly of infectious virions. J.
Virol. 76, 6729–6742.
Gianni, T., Campadelli-Fiume, G., Menotti, L., 2004. Entry of
herpes simplex virus mediated by chimeric forms of nectin 1
retargeted to endosomes or to lipid rafts occurs through acidic
endosomes. J. Virol. 78, 12268–12276.
Granzow, H., Klupp, B.G., Mettenleiter, T.C., 2004. The pseudora-
bies virus US3 protein is a component of primary and of mature
virions. J. Virol. 78, 1314–1323.
Granzow, H., Klupp, B.G., Mettenleiter, T.C., 2005. Entry of
pseudorabies virus: an immunogold labeling study. J. Virol.
79, 3200–3205.
Granzow, H., Klupp, B.G., Fuchs, W., Veits, J., Osterrieder, N.,
Mettenleiter, T.C., 2001. Egress of alphaherpesviruses: a com-
parative ultrastructural study. J. Virol. 75, 3675–3684.
Granzow, H., Weiland, F., Jons, A., Klupp, B.G., Karger, A.,
Mettenleiter, T.C., 1997. Ultrastructural analysis of the replica-
tion cycle of pseudorabies virus in cell culture: a reassessment. J.
Virol. 71, 2072–2082.
Gross, S., Harley, C., Wilson, D.W., 2003. The cytoplasmic tail of
herpes simplex virus glycoprotein H binds to the tegument
protein VP16 in vitro and in vivo. Virology 317, 1–
12.
Klupp, B.G., Granzow, H., Mettenleiter, T.C., 2001a. Effect of the
pseudorabies virus US3 protein on nuclear membrane localiza-
tion of the UL34 protein and virus egress from the nucleus. J.
Gen. Virol. 82, 2363–2371.
Klupp, B.G., Bottcher, S., Granzow, H., Kopp, M., Mettenleiter,
T.C., 2005. Complex formation between the UL16 and UL21
tegument proteins of pseudorabies virus. J. Virol. 79, 1510–
1522.
Klupp, B.G., Fuchs, W., Granzow, H., Nixdorf, R., Mettenleiter,
T.C., 2002. The pseudorabies virus UL36 tegument protein
physically interacts with the UL37 protein. J. Virol. 76,
3065–3071.
Klupp, B.G., Granzow, H., Mundt, E., Mettenleiter, T.C., 2001b.
Pseudorabies virus UL37 gene product is involved in secondary
envelopment. J. Virol. 75, 8927–8936.
Kopp, M., Granzow, H., Fuchs, W., Klupp, B.G., Mettenleiter, T.C.,
2004. Simultaneous deletion of pseudorabies virus tegument
protein UL11 and glycoprotein M severely impairs secondary
envelopment. J. Virol. 78, 3024–3034.
Kwong, A., Frenkel, N., 1989. The herpes simplex virus virion host
shutoff function. J. Virol. 63, 4834–4839.
Lake, C.M., Hutt-Fletcher, L.M., 2004. The Epstein-Barr virus
BFRF1 and BFLF2 proteins interact and coexpression alters
their cellular localization. Virology 320, 99–106.
Lam, N., Letchworth, G., 2000. Bovine herpesvirus 1 UL3.5 inter-
acts with bovine herpesvirus 1 a-transinducing factor. J. Virol.
74, 2876–2884.
Loomis, J.S., Courtney, R.J., Wills, J.W., 2003. Identification of
binding partners for the UL11 tegument protein of herpes
simplex virus type 1. J. Virol. 77, 11417–11424.
McLauchlan, J., Rixon, F.J., 1992. Characterization of enveloped
tegument structures (L-particles) produced by alphaherpes-
viruses: integrity of the tegument does not depend on the
presence of capsid or envelope. J. Gen. Virol. 73, 269–
276.
Mettenleiter, T.C., 2004. Budding events in herpesvirus morphogen-
esis. Virus Res. 106, 167–180.
Mettenleiter, T.C., 2002. Herpesvirus assembly and egress. J. Virol.
76, 1537–1547.
Mossman, K., Sherburne, R., Lavery, C., Duncan, J., Smiley, J.,
2000. Evidence that herpes simplex virus VP16 is required for
viral egress downstream of the initial envelopment event. J.
Virol. 74, 6287–6299.
Muranyi, W., Haas, J., Wagner, M., Krohne, G., Koszinowski, U.H.,
2002. Cytomegalovirus recruitment of cellular kinases to dis-
solve the nuclear lamina. Science 297, 854–857.
Nicola, A.V., Straus, S.E., 2004. Cellular and viral requirements for
rapid endocytic entry of herpes simplex virus. J. Virol. 78, 7508–
7517.
Purves, F., Spector, D., Roizman, B., 1992. UL34, the target of the
herpes simplex virus US3 protein kinase, is a membrane protein
which in its unphosphorylated state associates with novel phos-
phoproteins. J. Virol. 66, 4295–4303.
Reynolds, A., Wills, E.G., Roller, R., Ryckman, B.J., Baines, J.D.,
2002. Ultrastructural localization of the herpes simplex virus
type 1 UL31, UL34, and US3 proteins suggests specific roles in
primary envelopment and egress of nucleocapsids. J. Virol. 76,
8939–8952.
Reynolds, A., Liang, L., Baines, J.D., 2004. Conformational
changes in the nuclear lamina induced by herpes simplex
virus type 1 genes UL31 and UL34. J. Virol. 78, 5564–
5575.
Roizman, B., Knipe, D., 2001. Herpes simplex viruses and their
replication. In: Knipe, D., Howley, P.M. (Eds.), Fields Virology.
fourth ed. pp. 2399–2460.
Ryckman, B., Roller, R.J., 2004. Herpes simplex virus type 1
primary envelopment: the UL34 protein modification and the
US3-UL34 catalytic relationship. J. Virol. 78, 399–412.
Sanchez, V., Spector, D., 2002. CMV makes a timely exit. Science
297, 778–779.
Simpson-Holley, M., Baines, J., Roller, R., Knipe, D.M., 2004.
Herpes simplex virus 1 UL31 and UL34 gene products promote
the late maturation of viral replication compartments to the
nuclear periphery. J. Virol. 78, 5591–5600.
Spear, P.G., 1993. Entry of alphaherpesviruses into cells. Semin.
Virol. 4, 167–180.
Spear, P.G., Longnecker, R., 2003. Herpesvirus entry: an update. J.
Virol. 77, 10179–10185.
T.C. Mettenleiter / Veterinary Microbiology 113 (2006) 163–169 169
Spengler, M., Niesen, N., Grose, C., Ruyechan, W.T., Hay, J., 2001.
Interactions among structural proteins of varicella zoster virus.
Arch. Virol. 17 (Suppl.), 71–79.
Steven, A.C., Spear, P.G., 1997. Herpesvirus capsid assembly
and envelopment. In: Chiu, W., Burnett, R.M., Garcea, R.
(Eds.), Structural Biology of Viruses. Oxford University Press,
New York, pp. 312–351.
Zhou, Z., Chen, D., Jakana, J., Rixon, F.J., Chiu, W., 1999. Visua-
lization of tegument-capsid interactions and DNA in intact
herpes simplex virus type 1 virions. J. Virol. 73, 3210–3218.