scholarly journals Mutations in Herpes Simplex Virus Glycoprotein D Distinguish Entry of Free Virus from Cell-Cell Spread

2000 ◽  
Vol 74 (24) ◽  
pp. 11437-11446 ◽  
Author(s):  
Daniel A. Rauch ◽  
Nilda Rodriguez ◽  
Richard J. Roller
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Glycoprotein D ◽  
Free Virus ◽  
Herpes Simplex Virus Glycoprotein ◽  
Mediate Cell ◽  
Simplex Virus ◽  
Cell Spread ◽  
Hsv 1 ◽  
Cell Cell

ABSTRACT Herpes simplex virus type 1 (HSV-1) glycoprotein D (gD) is an essential component of the entry apparatus that is responsible for viral penetration and subsequent cell-cell spread. To test the hypothesis that gD may serve distinguishable functions in entry of free virus and cell-cell spread, mutants were selected for growth on US11cl19.3 cells, which are resistant to both processes due to the lack of a functional gD receptor, and then tested for their ability to enter as free virus and to spread from cell to cell. Unlike their wild-type parent, HSV-1(F), the variants that emerged from this selection, which were named SP mutants, are all capable of forming macroscopic plaques on the resistant cells. This ability is caused by a marked increase in cell-cell spread without a concomitant increase in efficiency of entry of free virus. gD substitutions that arose within these mutants are sufficient to mediate cell-cell spread in US11cl19.3 cells but are insufficient to overcome the restriction to entry of free virions. These results suggest that mutations in gD (i) are sufficient but not necessary to overcome the block to cell-cell spread exhibited by US11cl19.3 cells and (ii) are insufficient to mediate entry of free virus in the same cells.

scholarly journals Herpes Simplex Virus gE/gI Must Accumulate in the trans-Golgi Network at Early Times and Then Redistribute to Cell Junctions To Promote Cell-Cell Spread

2006 ◽  
Vol 80 (7) ◽  
pp. 3167-3179 ◽  
Author(s):  
Aaron Farnsworth ◽  
David C. Johnson
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Cell Junctions ◽  
Virus Spread ◽  
Neuronal Tissues ◽  
Mediate Cell ◽  
Simplex Virus ◽  
Golgi Network ◽  
Cell Spread ◽  
Cell Cell

ABSTRACT Herpes simplex virus (HSV) glycoprotein heterodimer gE/gI is necessary for virus spread in epithelial and neuronal tissues. Deletion of the relatively large gE cytoplasmic (CT) domain abrogates the ability of gE/gI to mediate HSV spread. The gE CT domain is required for the sorting of gE/gI to the trans-Golgi network (TGN) in early stages of virus infection, and there are several recognizable TGN sorting motifs grouped near the center of this domain. Late in HSV infection, gE/gI, other viral glycoproteins, and enveloped virions redistribute from the TGN to epithelial cell junctions, and the gE CT domain is also required for this process. Without the gE CT domain, newly enveloped virions are directed to apical surfaces instead of to cell junctions. We hypothesized that the gE CT domain promotes virus envelopment into TGN subdomains from which nascent enveloped virions are sorted to cell junctions, a process that enhances cell-to-cell spread. To characterize elements of the gE CT domain involved in intracellular trafficking and cell-to-cell spread, we constructed a panel of truncation mutants. Specifically, these mutants were used to address whether sorting to the TGN and redistribution to cell junctions are necessary, and sufficient, for gE/gI to promote cell-to-cell spread. gE-519, lacking 32 C-terminal residues, localized normally to the TGN early in infection and then trafficked to cell junctions at late times and mediated virus spread. By contrast, mutants gE-495 (lacking 56 C-terminal residues) and gE-470 (lacking 81 residues) accumulated in the TGN but did not traffic to cell junctions and did not mediate cell-to-cell spread. A fourth mutant, gE-448 (lacking most of the CT domain), did not localize to cell junctions and did not mediate virus spread. Therefore, the capacity of gE/gI to promote cell-cell spread requires early localization to the TGN, but this is not sufficient for virus spread. Additionally, gE CT sequences between residues 495 and 519, which contain no obvious cell sorting motifs, are required to promote gE/gI traffic to cell junctions and cell-to-cell spread.

scholarly journals Identification of Novel Immunodominant CD4+ Th1-Type T-Cell Peptide Epitopes from Herpes Simplex Virus Glycoprotein D That Confer Protective Immunity

2003 ◽  
Vol 77 (17) ◽  
pp. 9463-9473 ◽  
Author(s):  
Lbachir BenMohamed ◽  
Georges Bertrand ◽  
Cory D. McNamara ◽  
Helene Gras-Masse ◽  
Juergen Hammer ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
T Cell ◽  
Protective Immunity ◽  
Biologically Active ◽  
Glycoprotein D ◽  
Peptide Epitopes ◽  
Herpes Simplex Virus Glycoprotein ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT The molecular characterization of the epitope repertoire on herpes simplex virus (HSV) antigens would greatly expand our knowledge of HSV immunity and improve immune interventions against herpesvirus infections. HSV glycoprotein D (gD) is an immunodominant viral coat protein and is considered an excellent vaccine candidate antigen. By using the TEPITOPE prediction algorithm, we have identified and characterized a total of 12 regions within the HSV type 1 (HSV-1) gD bearing potential CD4+ T-cell epitopes, each 27 to 34 amino acids in length. Immunogenicity studies of the corresponding medium-sized peptides confirmed all previously known gD epitopes and additionally revealed four new immunodominant regions (gD49-82, gD146-179, gD228-257, and gD332-358), each containing naturally processed epitopes. These epitopes elicited potent T-cell responses in mice of diverse major histocompatibility complex backgrounds. Each of the four new immunodominant peptide epitopes generated strong CD4+ Th1 T cells that were biologically active against HSV-1-infected bone marrow-derived dendritic cells. Importantly, immunization of H-2d mice with the four newly identified CD4+ Th1 peptide epitopes but not with four CD4+ Th2 peptide epitopes induced a robust protective immunity against lethal ocular HSV-1 challenge. These peptide epitopes may prove to be important components of an effective immunoprophylactic strategy against herpes.

scholarly journals Herpes Simplex Virus Glycoprotein K, but Not Its Syncytial Allele, Inhibits Cell-Cell Fusion Mediated by the Four Fusogenic Glycoproteins, gD, gB, gH, and gL

2003 ◽  
Vol 77 (12) ◽  
pp. 6836-6844 ◽  
Author(s):  
Elisa Avitabile ◽  
Giulia Lombardi ◽  
Gabriella Campadelli-Fiume
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Cell Fusion ◽  
Vero Cells ◽  
Giant Cells ◽  
Glycoprotein K ◽  
Herpes Simplex Virus Glycoprotein ◽  
Simplex Virus ◽  
Hsv 1 ◽  
Cell Cell

ABSTRACT A Myc epitope was inserted at residue 283 of herpes simplex virus type 1 (HSV-1) glycoprotein K (gK), a position previously shown not to interfere with gK activity. The Myc-tagged gK localized predominantly to the endoplasmic reticulum, both in uninfected and in HSV-infected cells. gK, coexpressed with the four HSV fusogenic glycoproteins, gD, gB, gH, and gL, inhibited cell-cell fusion. The effect was partially dose dependent and was observed both in baby hamster kidney (BHK) and in Vero cells, indicating that the antifusion activity of gK may be cell line independent. The antifusion activity of gK did not require viral proteins other than the four fusogenic glycoproteins. A syncytial (syn) allele of gK (syn-gK) carrying the A40V substitution present in HSV-1(MP) did not block fusion to the extent seen with the wild-type (wt) gK, indicating that the syn mutation ablated, at least in part, the antifusogenic activity of wt gK. We conclude that gK is part of the mechanism whereby HSV negatively regulates its own fusion activity. Its effect accounts for the notion that cells infected with wt HSV do not fuse with adjacent, uninfected cells into multinucleated giant cells or syncytia. gK may also function to preclude fusion between virion envelope and the virion-encasing vesicles during virus transport to the extracellular compartment, thus preventing nucleocapsid de-envelopment in the cytoplasm.

scholarly journals Requirement of Interaction of Nectin-1α/HveC with Afadin for Efficient Cell-Cell Spread of Herpes Simplex Virus Type 1

2001 ◽  
Vol 75 (10) ◽  
pp. 4734-4743 ◽  
Author(s):  
Toshiaki Sakisaka ◽  
Tomokuni Taniguchi ◽  
Hiroyuki Nakanishi ◽  
Kenichi Takahashi ◽  
Masako Miyahara ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
L Cells ◽  
Simplex Virus ◽  
Cell Spread ◽  
Hsv 1 ◽  
Cell Cell

ABSTRACT We recently found a novel cell-cell adhesion system at cadherin-based adherens junctions (AJs), consisting at least of nectin, a Ca2+-independent homophilic immunoglobulin-like adhesion molecule, and afadin, an actin filament-binding protein that connects nectin to the actin cytoskeleton. Nectin is associated with cadherin through afadin and α-catenin. The cadherin-catenin system increases the concentration of nectin at AJs in an afadin-dependent manner. Nectin constitutes a family consisting of three members: nectin-1, -2, and -3. Nectin-1 serves as an entry and cell-cell spread mediator of herpes simplex virus type 1 (HSV-1). We studied here a role of the interaction of nectin-1α with afadin in entry and/or cell-cell spread of HSV-1. By the use of cadherin-deficient L cells overexpressing the full length of nectin-1α capable of interacting with afadin and L cells overexpressing a truncated form of nectin-1α incapable of interacting with afadin, we found that the interaction of nectin-1α with afadin increased the efficiency of cell-cell spread, but not entry, of HSV-1. This interaction did not affect the binding to nectin-1α of glycoprotein D, a viral component mediating entry of HSV-1 into host cells. Furthermore, the cadherin-catenin system increased the efficiency of cell-cell spread of HSV-1, although it also increased the efficiency of entry of HSV-1. It is likely that efficient cell-cell spread of HSV-1 is caused by afadin-dependent concentrated localization of nectin-1α at cadherin-based AJs.

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