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Arvin A, Campadelli-Fiume G, Mocarski E, et al., editors. Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis. Cambridge: Cambridge University Press; 2007.

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Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis.

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Fig. 3.3. Herpesvirus capsid at 8 Å resolution (Zhou et al.

Fig. 3.3

Herpesvirus capsid at 8 Å resolution (Zhou et al., 2000) and atomic model of upper domain of the HSV-1 major capsid protein (MCP), VP5 (Bowman et al., 2003). (a) Radially color-coded surface representation of the herpes simplex virus type 1 B capsid structure at 8.5 Å. One of the 20 triangular faces is denoted by dashed triangle. The penton and three types of hexons are indicated by ‘5’, P, E and C. Also labeled are the six quasi-equivalent triplexes, Ta, Tb, Tc, Td, Te, Tf. (b) Two hexon subunits were shown in wire frame representation with α helices identified in one of the VP5 subunit illustrated by orange cylinders (5 Å in diameter). The red arrowhead points to the 7 helix bundle in the middle domain and the white arrow identifies the long helix in the floor domain that connects adjacent subunits. (c) Ribbon representation of the atomic structure of the HSV-1 MCP upper domain determined by X-ray crystallography (Bowman et al., 2003). The helices identified in the hexon VP5 subunit in the 8.5 Å HSV1 capsid map (Zhou et al., 2000) are shown as cylinders: those in green match with helices present in the X-ray structure and those in yellow are absent in the X-ray model, suggesting possible structural differences of MCP packed in the crystal and inside the virion. (d) One single triplex is shown as shaded surface representation with individual subunits in different colors: VP19c in green and the two quasi-equivalent VP23 subunits in light and dark grey, all situated on the capsid shell domains of VP5 (blue). (e) α-helices identified in the two quasi-equivalent VP23 molecules (in red and yellow cylinders of 5 Å diameter, respectively). Adapted with permissions from publishers.

Fig. 3.4. Comparison of the three-dimensional structures of alpha, beta and gammaherpesvirus capsids.

Fig. 3.4

Comparison of the three-dimensional structures of alpha, beta and gammaherpesvirus capsids. The capsid maps of HSV-1 (a), HCMV (b) and KSHV (c) are shown as shaded surfaces colored according to particle radius and viewed along an icosahedral three-fold axis. The resolution of the HSV-1 and KSHV capsid maps is 24 Å and that of the HCMV capsid (Butcher et al., 1998) is 35 Å. The right two columns are detailed comparisons of a penton and an E hexon, which were extracted computationally from each map and shown in their top and side views.

Fig. 3.6. Difference of the anchored tegument proteins between HSV-1 ((a) and (b)) and HCMV ((c)–(e)).

Fig. 3.6

Difference of the anchored tegument proteins between HSV-1 ((a) and (b)) and HCMV ((c)–(e)). ((a) and (c)) Radially color-coded shaded surface views of the three-dimensional reconstruction of HSV-1 (a) and HCMV (c) virions as viewed along an icosahedral three-fold axis. The bulk of the tegument components and the viral envelope are not icosahedrally ordered or polymorphic, thus appearing as disconnected low densities in the icosahedral reconstruction. These disconnected densities were masked out for the right hemisphere to better reveal the icosahedrally ordered tegument proteins, which are shown in blue to purple colors in (a) and in purple in (c). ((b) and (d)) Close-up views of the region indicated in (a) and (c), respectively, showing the molecular interactions of the tegument proteins (yellow) with the penton (red), P hexon (blue) and triplexes (green). In HSV-1, contrary to the extensive tegument association with all hexons, the tegument densities do not interact with any hexon. (e) Extracted triplex HCMV Tc with its attached tegument densities. Three tegument densities interact with the upper domain of each triplex (insert Table 3.1).

Fig. 7.3. Ribbon diagram of the 3D structure of a soluble truncated form of gD (gD285t, colored in orange) bound to HVEM receptor (HveA, colored in green) as determined by X-ray crystallography.

Fig. 7.3

Ribbon diagram of the 3D structure of a soluble truncated form of gD (gD285t, colored in orange) bound to HVEM receptor (HveA, colored in green) as determined by X-ray crystallography. The N-terminus (residues 1–37) of gD is devoid of a specific structure when in the unbound state, but folds into a hairpin when bound to HVEM receptor. The β-strand formed by residues 27–29 (indicated with number 1) forms an intermolecular β-sheet with HVEM residues 35–37 (letter d). The core of gD (residues 56–184) has a V-type immunglobulin domain structure, composed of 9 parallel and antiparallel β-strands (letters A to G) that form two opposing β-sheets, and carries an additional α-helix (α1). The residues 185–259 form two α-helices that fold back to the N-ter (α2 and α3), and two β-strands (numbered 3 and 4). The α3 helix supports gD’s N-terminal hairpin. An additional β-strand (number 2) is located in the connector sequence (residues 33–55) that precedes the Ig-like core. Reprinted from (Carfi et al., 2001), with permission.

Fig. 8.2. The protein components of the HSV IE enhancer complex.

Fig. 8.2

The protein components of the HSV IE enhancer complex.

Oct-1: The transactivation (TA-Q and TA-S/T) and POU (POUs and POUh) domains are shown. The POU-specific box recognizes ATGC while the POU-homeobox recognizes TAAT within the enhancer core element (ATGCTAATGARAT). Proteins that bind to the Oct-1 POU domain are listed. The inherent flexibility of the POU domain and the potential orientations of the POUs box in recognition of the core element are depicted. In the schematic representation of the Oct-1 POU-homeobox, the residues which are important for the recognition by VP16 are indicated.

VP16: The structure and protein interactions of VP16 are represented. The core structure contains the clustered residues that are critical for the assembly of the IE enhancer complex (HCF-1, Oct-1, DNA) while the transactivation domain (TA, aa 412–490) interacts with a number of basal factors and chromatin modifying components. A schematic representation of the VP16 protein structure is shown (left) indicating the various protein interaction surfaces oriented in recognition of the Oct-1 POU-homeobox/ DNA complex.

HCF-1: The amino-terminal kelch, mid-aminoterminal, proteolytic processing (PPD), autocatalytic (Auto), transactivation (TA), WYF-rich, FN3 repeat, and nuclear localization signal (NLS) regions are represented. The proteins that interact with each region are listed below the appropriate domain. The PPD is represented as a series of consensus (large oval) and divergent (small oval) reiterations of the HCF-1 cleavage sequence shown above. (Bottom left) A stylized representation of the HCF-1 kelch domain is shown illustrating the seven predicted blades (antiparallel sheets, E1 through E4; loops, L1–2 through L4–1). For HCF-1, the predicted ring closure utilizes E4 from the animoterminus and E1-2-3 from the carboxyterminus of the domain (NH2 closure). (Bottom right) The derived molecular model of the HCF-1 kelch domain structure is depicted.

Sp1: The inhibitory domain (INH), transactivation domains (TA-1, TA-2), and DNA binding domains (C2H2, Zn fingers) are represented. Proteins or protein complexes that interact with Sp1 are listed. The structure of the C2H2 Zn finger domain is schematically represented: C, cysteine; H, histadine; F/Y, phenylalanine or tyrosine; y, hydrophobic residue. Light circles represent amino acids that are predicted to make DNA contacts.

GABP: The α subunit contains the ets DNA binding domain recognizing the GA box and the heterodimerization domain (α/β). The β subunit contains ankyrin repeats (α/β heterodimerization region), nuclear localization signals (NLS), transactivation domain (TA), and tetramerization sequences (β−β). The sequence of the transactivation domain is shown and the residues that are critical for both transactivation and interaction with HCF-1 are boxed. (see colour plate section)

Fig. 8.4. Model of the induction of the IE genes during HSV reactivation from latency.

Fig. 8.4

Model of the induction of the IE genes during HSV reactivation from latency. (Top) Immunohistochemistry studies of HCF-1 demonstrate that the protein is specifically sequestered in the cytoplasm of sensory neurons (0 time, middle panel) and rapidly transported to the nucleus under experimental conditions that reactivate HSV from latency (explant reactivation stimuli, right panel). (Bottom) Schematic depiction of the activation of IE enhancer components during the initiation of reactivation. Environmental signal(s) result in the release of cytoplasmically sequestered HCF-1 and the activation of DNA binding factors such as GABP, Sp1, or other factors which function in concert with HCF-1 to activate the IE genes and initiate the viral lytic cycle. (see colour plate section)

Fig. 12.1. Schematic drawing showing the two alternative pathways of alphaherpesvirus egress from infected cells.

Fig. 12.1

Schematic drawing showing the two alternative pathways of alphaherpesvirus egress from infected cells. The single envelopment pathway is depicted to the left, and the double envelopment, or de-envelopment-re-envelopment is depicted to the right of the illustration. The schematic drawing does not shows the gross ultrastructural modifications of the Golgi apparatus and TGN. Perinuclear virions and nuclear membranes are decorated with glycoproteins of different color than virions at the level of the Golgi apparatus and TGN, as well as extracellular virions, to emphasize that the oligosaccharide moieties of the viral glycoproteins are of the immature type in early exocytic compartment, but are of the mature type in the late exocytic compartments and in extracellular virions. The drawing considers also the possibility that nucleocapsids exit the nucleoplasm through modified nuclear pores, without transiting through the perinuclear lumen. (Drawing by courtesy of L. Menotti.)

Fig. 14.6. Three-dimensional reconstructions of (a) the HCMV B-capsid (adapted from Butcher et al.

Fig. 14.6

Three-dimensional reconstructions of (a) the HCMV B-capsid (adapted from Butcher et al., 1998; with permission from Academic Press), and (b) the HCMV virion (adapted from Zhou et al., 1999; with permission from the American Society for Microbiology). Both structures are viewed along the icosahedral twofold symmetry axes and are radially depth-cued so that darker regions are closer to the centre of the particle and lighter regions are further away.

Fig. 17.3. Comparison between the HCMV major immediate early (MIE) and the HHV-6 R3 enhancer.

Fig. 17.3

Comparison between the HCMV major immediate early (MIE) and the HHV-6 R3 enhancer. Viral genes and promoter/ transcription start sites are designated by an arrow. The HCMV also has a unique region and a modulator discussed in the text. The various transcription factor binding sites identified for HCMV and HHV-6 are designated. The AP-2 sites in the R3 enhancer are not identified.

Fig. 23.1. 3D structure of the KSHV capsid at 24-Å resolution by electron cryomicroscopy.

Fig. 23.1

3D structure of the KSHV capsid at 24-Å resolution by electron cryomicroscopy. The capsid is shown as shaded surface color-coded according to particle radius. The three structural component of the capsid are indicated, including 12 pentons (“5”), 150 hexons (“6”) and 320 triplexes (“t”). (Wu et al., 2000 with permission).

Fig. 24.4. Functional protein domains of EBNA1.

Fig. 24.4

Functional protein domains of EBNA1. Amino acid residues are indicated for the boundaries of protein domains for DNA binding, dimerization, chromosome binding sites (CBS), nuclear localization (NLS), or protein–protein interactions (as indicated).

Fig. 24.5. X-ray crystal structure of EBNA1 dimer bound to a consensus DNA recognition site (courtesy of Bocharev et al.

Fig. 24.5

X-ray crystal structure of EBNA1 dimer bound to a consensus DNA recognition site (courtesy of Bocharev et al., Cell in press). (a) Ribbon diagram showing the core domain (residues 504–607) from each monomer, in blue. Flanking domains are shown in yellow. (b) View down the non-crystallographic axis showing one monomer in white and the other in the same color scheme as used in (a). Proline loops are indicated by arrows.

Fig. 24.6. Model for OriP of EBV.

Fig. 24.6

Model for OriP of EBV. Indicated are protein–protein and protein DNA interactions that are required for the initiation of DNA synthesis at OriP.

Fig. 27.2. Latency Ⅲ pattern characteristic of the majority of cases of post-transplant lymphoproliferative disease.

Fig. 27.2

Latency Ⅲ pattern characteristic of the majority of cases of post-transplant lymphoproliferative disease. All known EBV latent genes are expressed in this form of latency: (a) EBERs, (b) EBNA1, (c) LMP1, (d) EBNA2.

Fig. 27.3. Latency pattern characteristic of Burkitt’s lymphoma (BL).

Fig. 27.3

Latency pattern characteristic of Burkitt’s lymphoma (BL). (a) Expression of EBERs in the tumor cells of BL tissue shown by isotopic in situ hybridization and (b) Immunoblotting demonstrating protein expression limited to EBNA1 in so-called ‘group I’ BL cell lines which recapitulate the in vivo expression profile. ‘Group Ⅲ’ BL lines have an expression pattern similar to that of LCLs (Latency Ⅲ) and represent cell lines that have ‘drifted’ from a latency I pattern in vitro.

Fig. 27.4. EBV latency type Ⅱ.

Fig. 27.4

EBV latency type Ⅱ. Left panel shows (a) Expression of EBERs, (b) EBNA1 and (c) LMP1, in the tumor cells of nasopharyngeal carcinoma (NPC). LMP1 expression is not a regular feature of these tumors. LMP2 protein has not yet been reported in NPC tumors, despite the detection of LMP2 RNA. Right panel shows EBV gene expression in the rare tumor cells of (HRS cells) Hodgkin’s lymphoma. (d) EBERs, (e) LMP1 and (f) LMP2. EBNA1 protein is also detectable in the majority of cases (not shown). In contrast to NPC, both LMP1 and LMP2 protein are almost always detectable in EBV-infected HRS cells.

Fig. 28.1. KSHV gene expression in PEL cell lines and biopsy samples.

Fig. 28.1

KSHV gene expression in PEL cell lines and biopsy samples. This Figure summarizes the expression of individual KSHV genes in PEL cells during latency and following reactivation of the lytic cycle by treatment with TPA, Na-butyrate or heterologous expression of RTA by transfection or transduction. Also included are results from in situ hybridization or immunohistochemistry studies on biopsy samples of KS, MCD or PEL tumors. As discussed in the text, the color-coding is based on a comparison of several reports that studied KSHV genes by Northern blot, real time PCR or DNA array. (See color plate section.)

  • Fig. 28.1. KSHV gene expression in PEL cell lines and biopsy samples. Latent gene
  • Fig. 28.1. KSHV gene expression in PEL cell lines and biopsy samples. Latent gene in B cells only
  • Fig. 28.1. KSHV gene expression in PEL cell lines and biopsy samples. Latent gene in KS spindle cells in vivo; early (in some studies delayed) expression kinetics in PEL cells in vitro
  • Fig. 28.1. KSHV gene expression in PEL cell lines and biopsy samples. Immediate–early gene as judged by cycloheximide resistance
  • Fig. 28.1. KSHV gene expression in PEL cell lines and biopsy samples. Very rapid onset of gene expression in at least 2 studies
  • Fig. 28.1. KSHV gene expression in PEL cell lines and biopsy samples. Early lytic transcript: TPA inducible, unaffected by PFA
  • Fig. 28.1. KSHV gene expression in PEL cell lines and biopsy samples. Delayed onset of gene expression
  • Fig. 28.1. KSHV gene expression in PEL cell lines and biopsy samples. Late gene expression profile
  • Fig. 28.1. KSHV gene expression in PEL cell lines and biopsy samples. Late gene expression profile confirmed by PAA sensitivity
  • Fig. 28.1. KSHV gene expression in PEL cell lines and biopsy samples. Discrepant results in different gene array studies

Fig. 30.3. The structure of the vCYC (purple), CDK6 (cyan), p18Inkb (yellow) complex from side (a) and top (b) views, compared to cellular cyclin A (purple), CDK2 (cyan) side (c) and top (d) views.

Fig. 30.3

The structure of the vCYC (purple), CDK6 (cyan), p18Inkb (yellow) complex from side (a) and top (b) views, compared to cellular cyclin A (purple), CDK2 (cyan) side (c) and top (d) views. Unlike cellular cyclins, the regulatory T-loop of CDK6 is excluded from interaction with vCYC but the PSTAIRE regulatory helix of CDK6 still forms an interface with vCYC, The PSTAIRE helix forms part of the ATP binding domain required for kinase activity while the T loop acts as a negative regulator of kinase activity and must be phosphorylated by cyclin-activating kinases (CAK) in cellular cyclin–CDK complexes. While CAK phosphorylation may enhance vCYC-CDK6 stability, displacement of the T loop by vCYC allows this complex to be active in the absence of CAK activity. The structure of vCYC-CDK6 also reveals loss of the binding pocket used by cyclin-dependent kinase inhibitors (CDKI) of the CIP1/KIP1 family. These and other features support experimental data showing the vCYC-CDK6 not only have a broader target range than cellular D-type cyclins but also escape many normal negative regulatory controls imposed on the cellular cyclin machinery. Reprinted with permission (Jeffrey et al., 2000).

Fig. 42.1. Immunofluorescent micrograph of HCMV-infected AEC.

Fig. 42.1

Immunofluorescent micrograph of HCMV-infected AEC. Telomerase life-extended human AEC were infected with HCMV. Cells were fixed and stained for the presence of HCMV protein, glycoprotein B (a late product; green) and a cellular marker of the trans-Golgi network (TGN46; red).

Fig. 42.2. Immunofluorescent micrograph of HCMV-infected MDM.

Fig. 42.2

Immunofluorescent micrograph of HCMV-infected MDM. MDM were infected with HCMV. Cells were fixed and stained for the presence of HCMV proteins, pp65 (an early product; green) and IE-2 (an immediate-early productl; red).

Fig. 45.4. Panel A: CMV replicates in diverse cell types in uterine decidua.

Fig. 45.4

Panel A: CMV replicates in diverse cell types in uterine decidua. CMV infects endometrial glands (GLD), uterine blood vessels (BV), resident decidual cells (DecC) and cytotrophoblasts (CTB) in the decidua. (a)–(c), Decidual biopsy specimens stained for CMV-infected-cell proteins (ICP, green) and cytokeratin (CK, red), which identified epithelial cells (EpC). (d)–(i), CMV-infected interstitial and endovascular CTB and DecC. (j)–(l), Endothelial cells (EnC) and smooth muscle cells (SMC) of uterine blood vessels (BV) are infected. Panel (b): Abundant innate immune cells infiltrating the decidua contain CMV proteins. (a)–(c) CMV gB (green), macrophages (Mϕ/DC, CD68, red). (d)–(f) DC-SIGN+ (green) macrophage/dendritic cells (Mϕ/DC) take up CMV gB (red). (g (and) h) CD56+ (green) natural killer (NK) cells target infection sites. (i) DC-SIGN+ cells containing gB. (j)–(l) Neutrophils (PMN) with phagocytosed proteins from virus-infected cells and endothelial cells (EnC) positive for von Willebrand factor (vWF) in blood vessels (BV). “Merged” indicates colocalized proteins (yellow). Large arrowheads indicate area shown in insets.

Fig. 45.5. (cont.

Fig. 45.5

(cont.)

Fig. 48.3. Immunobiological events during early primary HHV-6 infection and establishment of latency.

Fig. 48.3

Immunobiological events during early primary HHV-6 infection and establishment of latency.

Fig. 56.1. Latency genes of KSHV.

Fig. 56.1

Latency genes of KSHV. Transcripts of latent genes are depicted as arrows, superimposed on the physical map of the circular latent viral genome.

Fig. 61.3. Alignment of the KSHV and RRV genomes.

Fig. 61.3

Alignment of the KSHV and RRV genomes. The different colors signify ORFs contained in KSHV and RRV 26–95 that are conserved in the indicated herpesvirus subfamilies or subgroups. The square side of the symbol signifies the 5′ end and the pointed side of the symbol signifies the 3′ end of the depicted ORFs. The ORFs are not drawn to scale. (Taken from Alexander et al., 2000, with permission from the Journal of Virology.) (see colour plate section)

Fig. 62.1. Herpesvirus immunoevasins that directly interfere with class Ⅰ molecule biosynthesis.

Fig. 62.1

Herpesvirus immunoevasins that directly interfere with class Ⅰ molecule biosynthesis. MHC class Ⅰ molecules are assembled from free MHC class Ⅰ HC and β-2 microglobulin within the ER, along with antigenic peptide. Peptides are produced by cytosolic 4m proteasome degradation via its GAr domain. Tapasin and the PLC facilitate loading of peptide cargo onto empty class Ⅰ molecules. HSV ICP47 and HCMV US6 block TAP peptide transport, while HCMV US3 inhibits tapasin and retains class Ⅰ complexes in the ER. Following receipt of peptide, the loaded class Ⅰ molecules travel through the secretory pathway to the cell surface. HCMV US10 delays transport of class Ⅰ molecules from the ER, while VZV ORF66 and MCMV m152 retain class Ⅰ in the Golgi complex. HCMV US2, US11 and MHV γ68 MK3 dislocate class Ⅰ molecules via an unidentified ER membrane pore to the cytosol. The dislocated class Ⅰ heavy chains are ubiquinated (Ub) and deglycolylated by cellular PNGase prior to proteasomal cleavage. HHV-7 U21, MCMV m6, and HHV-8 K3 redirect class Ⅰ molecules from the secretory to the endolysosomal pathway for degradation. HHV-8 K5 likewise targets MHC class Ⅰ, B7-2 and ICAM-1 molecules to the endolysosmal pathway for destruction. MCMV m4 disrupts recognition of cell surface-disposed MHC class Ⅰ-peptide complexes by the TCR 8of CD8+ T-cells.

Fig. 65.1. Clinical appearance of varicella and herpes zoster.
Fig. 65.1. Clinical appearance of varicella and herpes zoster.

Fig. 65.1

Clinical appearance of varicella and herpes zoster. (a) Typical generalized vesicular rash of chickenpox in an adult. (b) Typical dermatomal papulo-vesicular rash of shingles in an adult.

Fig. 74.1. Generation of cell-mediated immune response.

Fig. 74.1

Generation of cell-mediated immune response.

Copyright © Cambridge University Press 2007.
Bookshelf ID: NBK47443

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