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PubMed2002

Expression and roles of herpesvirus entry mediators A and C in cells of oral origin.

The roles of viral glycoprotein D (gD) and cellular herpesvirus entry mediators A (HveA) and C (HveC) in herpes simplex virus entry into oral cells were determined. Studies with purified truncated forms of gD-1, HveA and HveC indicated that these molecules may be involved in herpes simplex virus entry into oral cells. Moreover, HveA was expressed similarly in primary cultures of gingival keratinocytes and fibroblasts, whereas HveC was expressed at higher levels in gingival keratinocytes, as determined by RT-PCR and immunocytochemical staining. Further analysis using immunohistochemistry demonstrated that both HveA and HveC were expressed in epithelial cells, fibroblasts and vascular endothelial cells in gingival tissues. However, only HveC was detected in nerve fibers. Also, HveA was detected throughout the epidermis, whereas HveC was pronounced in the strata basale and spinosum. In conclusion, this study characterized HveA and HveC, molecules that may participate in entry of herpes simplex virus into oral cells.

Adult↗
PubMed2006

Cluster analysis of immunohistochemical profiles in synovial sarcoma, malignant peripheral nerve sheath tumor, and Ewing sarcoma.

As a result of overlapping morphologic and immunohistochemical features, it can be difficult to distinguish synovial sarcoma, malignant peripheral nerve sheath tumor, and Ewing sarcoma/primitive neuroectodermal tumor in core biopsies. To analyze and compare immunohistochemical profiles, we stained tissue microarrays of 23 synovial sarcomas, 23 malignant peripheral nerve sheath tumors, and 27 Ewing sarcomas with 22 antibodies potentially useful in the differential diagnosis, and analyzed the data with cluster analysis. Stain intensity was scored as none, weak, or strong. For CD99, tumors with membranous accentuation were independently categorized. Cluster analysis sorted five groups, with like tumors clustering together. Synovial sarcoma clustered into two groups: one cytokeratin and EMA positive (n = 11), the other mostly cytokeratin negative, EMA positive, bcl-2 positive and mostly CD56 positive (n = 9). Malignant peripheral nerve sheath tumor clustered into two groups: one S100 positive, with nestin and NGFR positivity in most (n = 10), the other mostly S100 negative, and variably but mostly weakly positive for nestin and NGFR (n = 11). Ewing sarcomas clustered into a single group driven by membranous CD99 staining. Thirteen cases failed to cluster (outliers), while three Ewing sarcomas clustered into groups of other tumor types. Paired antibodies for each tumor type determined by visual assessment of cluster analysis data and statistical calculations of specificity, sensitivity, and predictive values showed that EMA/CK7 for synovial sarcoma, nestin/S100 for malignant peripheral nerve sheath tumor, and membranous CD99/Fli-1 for Ewing sarcoma yielded high specificity and positive predictive values. Cluster analysis also highlighted aberrant staining reactions and diagnostic pitfalls in these tumors. Hierarchical cluster analysis is an effective method for analyzing high-volume immunohistochemical data.

12E7 Antigen↗
PubMed2001

Mutation of PVRL1 is associated with sporadic, non-syndromic cleft lip/palate in northern Venezuela.

Non-syndromic cleft lip with or without cleft palate (CL/P, MIM 119530) is among the most common of major birth defects. Homozygosity for a nonsense mutation of PVRL1, W185X, results in an autosomal recessive CL/P syndrome on Margarita Island, CLPED1 (ref. 1). Here we demonstrate highly significant association between heterozygosity for this mutation and sporadic, non-syndromic CL/P in northern Venezuela.

Cell Adhesion Molecules↗
PubMed2005

Are innate immune signaling pathways in plants and animals conserved?

Although adaptive immunity is unique to vertebrates, the innate immune response seems to have ancient origins. Common features of innate immunity in vertebrates, invertebrate animals and plants include defined receptors for microbe-associated molecules, conserved mitogen-associated protein kinase signaling cascades and the production of antimicrobial peptides. It is commonly reported that these similarities in innate immunity represent a process of divergent evolution from an ancient unicellular eukaryote that pre-dated the divergence of the plant and animal kingdoms. However, at present, data suggest that the seemingly analogous regulatory modules used in plant and animal innate immunity are a consequence of convergent evolution and reflect inherent constraints on how an innate immune system can be constructed.

Adaptor Proteins, Vesicular Transport↗
PubMed2025

Modulating the PPARγ pathway upregulates NECTIN4 and enhances chimeric antigen receptor (CAR) T cell therapy in bladder cancer.

With the approval of the antibody-drug conjugate enfortumab vedotin (EV), NECTIN4 has emerged as a bona fide therapeutic target in urothelial carcinoma (UC). Here, we report the development of a NECTIN4-directed chimeric antigen receptor (CAR) T cell, which exhibits reactivity across cells expressing a range of endogenous NECTIN4, with enhanced activity in high expressors. We demonstrate that the PPARγ pathway, critical for luminal differentiation, transcriptionally controls NECTIN4, and that the PPARγ agonist rosiglitazone primes and augments NECTIN4 expression, thereby increasing sensitivity to NECTIN4-CAR T cell-mediated killing. NECTIN4-CAR T cells have potent anti-tumor activity even against EV resistant cells, which largely retain NECTIN4 expression, including in a post-EV biopsy cohort. Our results elucidate a therapeutically actionable mechanism that UC cells use to control NECTIN4 expression and suggest therapeutic approaches that leverage PPARγ agonists for rational combinations with NECTIN4-targeting agents in UC, as well as future potential treatment options for EV-refractory patients.

Humans↗
PubMed2006

The herpesvirus glycoproteins B and H.L are sequentially recruited to the receptor-bound gD to effect membrane fusion at virus entry.

Four glycoproteins (gD, gB, gH, and gL) are required for herpes simplex virus entry into the cell or for cell-cell fusion in transfected cells. gD serves as the receptor-binding glycoprotein and as the trigger of fusion; the other three execute fusion between the viral envelope and the plasma and endocytic membranes or the membranes of adjacent cells and are highly conserved among members of the herpesvirus family. Details of the interaction of gD with gB, gH, and gL were not known. Here, we report that the four glycoproteins assemble into a complex initiated by the interaction of gD with its cellular receptor. gB is recruited to the gD-receptor complex next, even in the absence of gH.gL. gH.gL is recruited next, but only to the receptor-gD-gB ensemble. A complex with the composition receptor-gD-gB-gH.gL is assembled transiently with a life span of 15-30 min in cells exposed to virus but can also be found in infected cells and in cells committed to form polykaryocytes after transfection of the glycoprotein quartet. The results indicate that the complex assembly is a critical step in the process of virus entry and fusion, and that no viral protein other than those that participate in the complex itself is required for complex assembly. These findings imply critical protein-protein interactions among the quartet as herpes simplex virions enter the cells and at cell-cell fusion, define a specific order of recruitment, and place gH.gL as the last link in the process of glycoprotein recruitment to the complex.

Animals↗
PubMed2000

The murine homolog of human Nectin1delta serves as a species nonspecific mediator for entry of human and animal alpha herpesviruses in a pathway independent of a detectable binding to gD.

The full-length cDNA of the murine homolog of human nectin1delta (mNectin1delta), also known as human poliovirus receptor related 1 (PRR1) or herpesvirus entry mediator C, was cloned and showed a >90% identity with its human counterpart. mNectin1delta is expressed in some murine cell lines, exemplified by NIH 3T3 and L cells, and in murine tissues. It mediates entry of an extended range of herpes simplex virus (HSV) strains, porcine pseudorabies virus (PrV), and bovine herpesvirus 1. A soluble form of the mediator blocked infectivity in mNectin1delta and human nectin1delta (hNectin1delta)-expressing cells, suggesting a physical interaction of the mediator with virions. The higher concentrations of soluble mNectin1 required to block infectivity relative to soluble hNectin1 suggest that the target of the two molecules is not identical. Entry of HSV, but not PrV, was blocked by soluble mNectin1delta in NIH 3T3 and L cells. Two features were unexpected. First, soluble mNectin1delta failed to physically interact with HSV glycoprotein D (gD) at a detectable level, although it interacted physically with virions. Second, coexpression of mNectin1delta and HSV gD did not restrict HSV or PrV infection, whereas coexpression of hNectin and gD did restrict infection, suggesting that mNectin1delta fails to be sequestered by HSV gD. We conclude that mNectin1delta serves as a species-nonspecific mediator for entry of the human and animal alphaherpesviruses. This activity, at least for HSV, is independent of a detectable binding to gD.

3T3 Cells↗
PubMed2006

Alpha-herpesvirus glycoprotein D interaction with sensory neurons triggers formation of varicosities that serve as virus exit sites.

Alpha-herpesviruses constitute closely related neurotropic viruses, including herpes simplex virus in man and pseudorabies virus (PRV) in pigs. Peripheral sensory neurons, such as trigeminal ganglion (TG) neurons, are predominant target cells for virus spread and lifelong latent infections. We report that in vitro infection of swine TG neurons with the homologous swine alpha-herpesvirus PRV results in the appearance of numerous synaptophysin-positive synaptic boutons (varicosities) along the axons. Nonneuronal cells that were juxtaposed to these varicosities became preferentially infected with PRV, suggesting that varicosities serve as axonal exit sites for the virus. Viral envelope glycoprotein D (gD) was found to be necessary and sufficient for the induction of varicosities. Inhibition of Cdc42 Rho GTPase and p38 mitogen-activated protein kinase signaling pathways strongly suppressed gD-induced varicosity formation. These data represent a novel aspect of the cell biology of alpha-herpesvirus infections of sensory neurons, demonstrating that virus attachment/entry is associated with signaling events and neuronal changes that may prepare efficient egress of progeny virus.

Animals↗
PubMed2004

Herpes simplex virus type 1 infection of polarized epithelial cells requires microtubules and access to receptors present at cell-cell contact sites.

Mucosal epithelia are invaded from the apical surface during a primary infection by herpes simplex virus type 1 (HSV-1). HSV-1 progeny virus, synthesized from latently infected peripheral neurons that innervate such epithelia, reinfects the epithelia most likely from the basolateral surface. The epithelial cell lines MDCK and Caco-2 can be induced in vitro to differentiate into polarized cells with distinct apical and plasma membrane domains separated by tight junctions if they are cultured on porous membrane filters. Our data using these culture systems showed that highly polarized epithelial cells were not susceptible to apical HSV-1 infection. However, HSV-1 infected these cells if added from the basolateral surface or if a depletion of extracellular Ca(2+) had weakened the strength of the cell-cell contacts. Basolateral infection and apical infection after the Ca(2+) switch required an intact microtubule network for genome targeting to the nucleus. This system can be used to identify the microtubule motors that HSV-1 uses during virus entry in polarized epithelial cells.

Animals↗
PubMed2006

Study of the PVRL1 gene in Italian nonsyndromic cleft lip patients with or without cleft palate.

Nonsyndromic cleft lip with or without cleft palate (CL/P) is a complex genetic trait and little is known about its aetiology. Recent investigations on rare clefting syndromes provided interesting clues about genes involved in face development. The PVRL1 gene encodes nectin1, a cell-to-cell adhesion molecule. Mutations in its sequence have been shown to cause the rare autosomal recessive syndrome CL/P-ectodermal dysplasia syndrome (CLPED1), while heterozygosity for the mutation W185X seemed to increase the risk of non syndromic CL/P in a population from northern Venezuela. In the present study, we screened 143 Italian CL/P patients for mutations in PVRL1. Three rare sequence variants in exon 3 that create amino-acid changes were detected in a total of 7 patients. Two of these mutations were not found in a panel of 292 unaffected controls, while the third was found in two controls. This study describes new mutations that may represent genetic risk factors for CL/P. Even though a study to look at the effects of the mutations on nectin1 function was not feasible, supporting evidence was reported, thus confirming the involvement of PVRL1 in the aetiology of non-syndromic CL/P malformation.

Cell Adhesion Molecules↗
PubMed1998

Entry of alphaherpesviruses mediated by poliovirus receptor-related protein 1 and poliovirus receptor.

A human member of the immunoglobulin superfamily was shown to mediate entry of several alphaherpesviruses, including herpes simplex viruses (HSV) 1 and 2, porcine pseudorabies virus (PRV), and bovine herpesvirus 1 (BHV-1). This membrane glycoprotein is poliovirus receptor-related protein 1 (Prr1), designated here as HveC. Incubation of HSV-1 with a secreted form of HveC inhibited subsequent infection of a variety of cell lines, suggesting that HveC interacts directly with the virus. Poliovirus receptor (Pvr) itself mediated entry of PRV and BHV-1 but not of the HSV strains tested. HveC was expressed in human cells of epithelial and neuronal origin; it is the prime candidate for the coreceptor that allows both HSV-1 and HSV-2 to infect epithelial cells on mucosal surfaces and spread to cells of the nervous system.

Alphaherpesvirinae↗
PubMed1998

Maturation of the arginine-specific proteases of Porphyromonas gingivalis W50 is dependent on a functional prR2 protease gene.

The prpR1 of Porphyromonas gingivalis codes for three distinct enzymes with specificity for arginyl peptide bonds termed RI, RIA, and RIB. These three isoforms comprise the majority of the extracellular, arginine-specific protease activity in P. gingivalis W50. RI is a heterodimer in which the catalytic alpha chain is noncovalently associated with a second chain involved in adherence phenomena. RIA and RIB are both monomeric species. RIA represents the free alpha chain, and RIB is a highly posttranslationally modified form of the alpha chain which is exclusively vesicle or membrane associated and migrates as a diffuse band on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. In previous studies, insertional inactivation of the prpR1 demonstrated that arginine-specific protease activity can also arise from a closely related second gene, prR2. In the present work, the prR2 was insertionally inactivated in P. gingivalis W50 in order to establish the contribution of this locus to the arginine-specific protease activity of this periodontal bacterium. Loss of prR2 function had several effects on prpR1-derived enzymes. First, the total Arg-X activity was reduced by approximately 50% relative to that of the parent strain. The reduction in total activity was a consequence of decreased concentrations of the monomeric enzymes derived from the prpR1, while the heterodimeric enzyme, RI, was unaffected by this mutation. Second, the chromatographic behavior of both the soluble and vesicle- or membrane-associated monomeric enzymes was radically different from the behavior of RIA and RIB from the parent strain. Finally, the vesicle- or membrane-associated enzyme in the prR2 mutant strain lacked the extensive posttranslational additions which are found on RIB in P. gingivalis W50. These data suggest that the product(s) of the prR2 plays a significant role in the maturation pathway of prpR1-derived enzymes, and this may contribute to the coconservation of these two genes in P. gingivalis.

Adhesins, Bacterial↗
PubMed1998

Herpes simplex virus glycoprotein D can bind to poliovirus receptor-related protein 1 or herpesvirus entry mediator, two structurally unrelated mediators of virus entry.

Several cell membrane proteins have been identified as herpes simplex virus (HSV) entry mediators (Hve). HveA (formerly HVEM) is a member of the tumor necrosis factor receptor family, whereas the poliovirus receptor-related proteins 1 and 2 (PRR1 and PRR2, renamed HveC and HveB) belong to the immunoglobulin superfamily. Here we show that a truncated form of HveC directly binds to HSV glycoprotein D (gD) in solution and at the surface of virions. This interaction is dependent on the native conformation of gD but independent of its N-linked glycosylation. Complex formation between soluble gD and HveC appears to involve one or two gD molecules for one HveC protein. Since HveA also mediates HSV entry by interacting with gD, we compared both structurally unrelated receptors for their binding to gD. Analyses of several gD variants indicated that structure and accessibility of the N-terminal domain of gD, essential for HveA binding, was not necessary for HveC interaction. Mutations in functional regions II, III, and IV of gD had similar effects on binding to either HveC or HveA. Competition assays with neutralizing anti-gD monoclonal antibodies (MAbs) showed that MAbs from group Ib prevented HveC and HveA binding to virions. However, group Ia MAbs blocked HveC but not HveA binding, and conversely, group VII MAbs blocked HveA but not HveC binding. Thus, we propose that HSV entry can be mediated by two structurally unrelated gD receptors through related but not identical binding with gD.

Amino Acid Sequence↗
PubMed2000

Nectin2alpha (PRR2alpha or HveB) and nectin2delta are low-efficiency mediators for entry of herpes simplex virus mutants carrying the Leu25Pro substitution in glycoprotein D.

The receptors for entry of herpes simplex viruses 1 and 2 (HSV-1 and -2), widely expressed in human cell lines, are members of a subset of the immunoglobulin superfamily exemplified by herpesvirus entry mediator C (HveC) and the herpesvirus immunoglobulin-like receptor (HIgR). This report focuses on two members of this subset, herpesvirus entry mediator B (HveB), recently designated nectin2/PRR2alpha, and its splice variant isoform, nectin2/PRR2delta. Nectin2alpha and -delta share the ectodomain but differ in the transmembrane and cytoplasmic regions. HveB was reported to enable entry of HSV-1 carrying mutations in glycoprotein D (gD) and of HSV-2, but not of wild-type (wt) HSV-1. We report that (i) both nectin2alpha and -delta served as receptors for the entry of HSV-1 mutant viruses HSV-1(U10) and -(U21) and AP7(r) that carry the Leu25Pro substitution in gD but not for HSV-1 mutants U30 and R5000 that carry the Ser140 or Ala185 substitution in gD. All of these mutants were able to overcome the block to entry mediated by expression of wt gD. (ii) Infection of cells expressing nectin2alpha or -delta required exposure to multiplicities of infection about 100-fold higher than those required to infect cells expressing HveC or HIgR. (iii) gD from HSV-1(U21) bound in vitro soluble forms of nectin2. The association was weaker than that to the soluble form of HveC/HIgR. Binding of wt HSV-1 gD to soluble nectin2 was not detectable. (iv) A major region of nectin2 functional in virus entry mapped to the V domain, located at the N terminus.

Amino Acid Substitution↗
PubMed2000

Cell-to-cell spread of wild-type herpes simplex virus type 1, but not of syncytial strains, is mediated by the immunoglobulin-like receptors that mediate virion entry, nectin1 (PRR1/HveC/HIgR) and nectin2 (PRR2/HveB).

The immunoglobulin-like receptors that mediate entry of herpes simplex virus type 1 (HSV-1) into human cells were found to mediate the direct cell-to-cell spread of wild-type virus. The receptors here designated Nectin1alpha and -delta and Nectin2alpha were originally designated HIgR, PRR1/HveC, and PRR2alpha/HveB, respectively. We report the following. (i) Wild-type HSV-1 spreads from cell to cell in J cells expressing nectin1alpha or nectin1delta but not in parental J cells that are devoid of entry receptors. A monoclonal antibody to nectin1, which blocks entry, also blocked cell-to-cell spread in nectin1-expressing J cells. Moreover, wild-type virus did not spread from a receptor-positive to a receptor-negative cell. (ii) The antibody to nectin1 blocked transmission of wild-type virus in a number of human cell lines, with varying efficiencies, suggesting that nectin1 is the principal mediator of wild-type virus spread in a variety of human cell lines. (iii) Nectin1 did not mediate cell fusion induced by the syncytial strains HSV-1(MP) and HFEM-syn. (iv) Nectin2alpha could serve as a receptor for spread of a mutant virus carrying the L25P substitution in glycoprotein D, but not of wild-type virus, in agreement with its ability to mediate entry of the mutant but not of wild-type virus.

Antibodies, Monoclonal↗
PubMed2003

Tissue-specific replicating capacity of a chimeric poliovirus that carries the internal ribosome entry site of hepatitis C virus in a new mouse model transgenic for the human poliovirus receptor.

Nucleotides (nt) 108 to 742 of an infectious cDNA clone of poliovirus (PV) Mahoney strain, including the corresponding region of the internal ribosome entry site (IRES), was replaced by nt 28 to 710 of hepatitis C virus (HCV) cDNA corresponding to the whole HCV IRES. A chimeric PV (2A-369) was generated by transfecting mammalian cells with an RNA transcribed in vitro from the cDNA. To examine replicating capacity of virus 2A-369 in the brain and liver of a mouse model for poliomyelitis, a new mouse model (MPVRTg25-61) that is transgenic for human PV receptor (hPVR; CD155) was generated in order to obtain a higher expression level of hPVR in the liver than those of hPVRTg mouse lines generated by us so far. The transgene used was constructed by combining a putative regulatory region of the mouse PVR homolog and the whole structural region of the hPVR gene. Virus 2A-369 replicated well in the liver of MPVRTg25-61 but not in the brain, whereas control Mahoney virus replicated well both in the liver and in the brain. The data suggest that the HCV IRES works more efficiently in the liver than in the brain and that PV IRES works well both in the liver and in the brain. The results support the notion that tissue-specific activity of IRES may be reflected in tissue tropism of a virus whose specific translation initiation is driven by IRES, that is, an IRES-dependent virus tropism.

Animals↗
PubMed2003

The domains of glycoprotein D required to block apoptosis induced by herpes simplex virus 1 are largely distinct from those involved in cell-cell fusion and binding to nectin1.

Glycoprotein D (gD) interacts with two alternative protein receptors, nectin1 and HveA, to mediate herpes simplex virus (HSV) entry into cells. Fusion of the envelope with the plasma membrane requires, in addition to gD, glycoproteins gB, gH, and gL. Coexpression of the four glycoproteins (gD, gB, gH, and gL) promotes cell-cell fusion. gD delivered in trans is also capable of blocking the apoptosis induced by gD deletion viruses grown either in noncomplementing cells (gD(-/-)) or in complementing cells (gD(-/+)). While ectopic expression of cation-independent mannose-6 phosphate receptor blocks apoptosis induced by both stocks, other requirements differ. Thus, apoptosis induced by gD(-/-) virus is blocked by full-length gD (or two gD fragments reconstituting a full-length molecule), whereas ectopic expression of the gD ectodomain is sufficient to block apoptosis induced by gD(-/+) virus. In this report we took advantage of a set of gD insertion-deletion mutants to map the domains of gD required to block apoptosis by gD(-/-) and gD(-/+) viruses and those involved in cell-cell fusion. The mutations that resulted in failure to block apoptosis were the same for gD(-/-) and gD(-/+) viruses and were located in three sites, one within the immunoglobulin-type core region (residues 125, 126, and 151), one in the upstream connector region (residues 34 and 43), and one in the C-terminal portion of the ectodomain (residue 277). A mutant that carried amino acid substitutions at the three glycosylation sites failed to block apoptosis but behaved like wild-type gD in all other assays. The mutations that inhibited polykaryocyte formation were located in the upstream connector region (residues 34 and 43), at the alpha1 helix (residue 77), in the immunoglobulin core and downstream regions (residue 151 and 187), and at the alpha3 helix (residues 243 and 246). Binding of soluble nectin1-Fc to cells expressing the mutant gDs was generally affected by the same mutations that affected fusion, with one notable exception (Delta277-310), which affected fusion without hampering nectin1 binding. This deletion likely identifies a region of gD involved in fusion activity at a post-nectin1-binding step. We conclude that whereas mutations that affected all functions (e.g., upstream connector region and residue 151) may be detrimental to overall gD structure, the mutations that affect specific activities identify domains of gD involved in the interactions with entry receptors and fusogenic glycoproteins and with cellular proteins required to block apoptosis. The evidence that glycosylation of gD is required for blocking apoptosis supports the conclusion that the interacting protein is the mannose-6 phosphate receptor.

Animals↗