scholarly journals Cell-to-cell spread inhibiting antibodies constitute a correlate of protection against Herpes Simplex Virus Type 1 reactivations

2020 ◽  
Author(s):  
Susanne Wolf ◽  
Mira Alt ◽  
Robin Dittrich ◽  
Miriam Dirks ◽  
Leonie Schipper ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Blood Donors ◽  
Vaccine Development ◽  
Natural Infection ◽  
Herpes Simplex Viruses ◽  
Correlate Of Protection ◽  
Simplex Virus ◽  
Cell Spread ◽  
Hsv 1

AbstractHerpes simplex viruses (HSV) cause ubiquitous human infections. For vaccine development, knowledge concerning correlates of protection against HSV is essential. Therefore, we investigated if humans principally can produce highly protective cell-to-cell spread inhibiting antibodies upon natural infection and whether such antibody responses correlate with protection from HSV reactivation. We established a high-throughput HSV-1 GFP reporter virus-based assay and screened 2496 human plasma samples for HSV-1 cell-to-cell spread inhibiting antibodies. We conducted a survey among the blood donors to analyze the correlation between the presence of cell-to-cell spread inhibiting antibodies in plasma and the frequency of HSV reactivations. In total, 128 of 2496 blood donors (5.1 %) exhibited high levels of HSV-1 cell-to-cell spread inhibiting antibodies in the plasma. Such individuals showed a significantly lower frequency of HSV reactivations compared to subjects without sufficient levels of HSV-1 cell-to-cell spread inhibiting antibodies. This study provides two important findings: (I) a fraction of humans produce HSV cell-to-cell spread inhibiting antibodies upon natural infection and (II) such antibodies correlate with protection against recurrent HSV. Moreover, these elite neutralizers can provide promising material for hyperimmunoglobulin, the isolation of superior antiviral antibodies and information for the design of a vaccine against HSV.ImportanceHerpes simplex virus 1 infections can cause painful mucosal lesions at the oral or genital tract and severe, life threatening disease in immunosuppressed patients or neonates. There is no approved vaccine available, and the emergence of drug resistances especially in long time treated patients makes the treatment increasingly difficult. We tested 2496 people for HSV-1 cell-to-cell spread inhibiting antibodies. Five percent exhibited functional titers such antibodies and showed significantly lower risk of reactivations, uncovering cell-to-cell spread inhibiting antibodies as a correlate of protection against Herpes simplex virus reactivations. Isolation of the cell-to-cell spread inhibiting antibodies from B-cells of these donors may contribute to develop novel antibody-based interventions for prophylactic and therapeutic use and provide starting material for vaccine development.

scholarly journals Herpes Simplex Virus with Highly Reduced gD Levels Can Efficiently Enter and Spread between Human Keratinocytes

2001 ◽  
Vol 75 (21) ◽  
pp. 10309-10318 ◽  
Author(s):  
Mary T. Huber ◽  
Todd W. Wisner ◽  
Nagendra R. Hegde ◽  
Kimberley A. Goldsmith ◽  
Daniel A. Rauch ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Cultured Cells ◽  
Human Keratinocytes ◽  
Hacat Cells ◽  
Wild Type ◽  
Simplex Virus ◽  
Cell Spread ◽  
Hsv 1

ABSTRACT The rapid spread of herpes simplex virus type 1 (HSV-1) in mucosal epithelia and neuronal tissue depends primarily on the ability of the virus to navigate within polarized cells and the tissues they constitute. To understand HSV entry and the spread of virus across cell junctions, we have previously characterized a human keratinocyte cell line, HaCaT. These cells appear to reflect cells infected in vivo more accurately than many of the cultured cells used to propagate HSV. HSV mutants lacking gE/gI are highly compromised in spread within epithelial and neuronal tissues and also show defects in cell-to-cell spread in HaCaT cells, but not in other, nonpolarized cells. HSV gD is normally considered absolutely essential for entry and cell-to-cell spread, both in cultured cells and in vivo. Here, an HSV-1 gD mutant virus, F-US6kan, was found to efficiently enter HaCaT cells and normal human keratinocytes and could spread from cell to cell without gD provided by complementing cells. By contrast, entry and spread into other cells, especially highly transformed cells commonly used to propagate HSV, were extremely inefficient. Further analyses of F-US6kan indicated that this mutant expressed extraordinarily low (1/500 wild-type) levels of gD. Neutralizing anti-gD monoclonal antibodies inhibited entry of F-US6kan, suggesting F-US6kan utilized this small amount of gD to enter cells. HaCaT cells expressed high levels of an HSV gD receptor, HveC, and entry of F-US6kan into HaCaT cells could also be inhibited with antibodies specific for HveC. Interestingly, anti-HveC antibodies were not fully able to inhibit entry of wild-type HSV-1 into HaCaT cells. These results help to uncover important properties of HSV and human keratinocytes. HSV, with exceedingly low levels of a crucial receptor-binding glycoprotein, can enter cells expressing high levels of receptor. In this case, surplus gD may be useful to avoid neutralization by anti-gD antibodies.

scholarly journals Herpes Simplex Virus 1 Spread in Oligodendrocytic Cells Is Highly Dependent on MAL Proteolipid

2019 ◽  
Vol 94 (4) ◽  
Author(s):  
José Antonio López-Guerrero ◽  
Carmen de la Nuez ◽  
Beatriz Praena ◽  
Enrique Sánchez-León ◽  
Claude Krummenacher ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Critical Role ◽  
Herpes Simplex Virus 1 ◽  
Cell Contacts ◽  
Viral Spread ◽  
First Case ◽  
Simplex Virus ◽  
Cell Spread ◽  
Hsv 1

ABSTRACT Myelin and lymphocyte protein (MAL) is a tetraspan integral membrane protein that resides in detergent-insoluble membrane fractions enriched in condensed membranes. MAL is expressed in oligodendrocytes, in Schwann cells, where it is essential for the stability of myelin, and at the apical membrane of epithelial cells, where it has a critical role in transport. In T lymphocytes, MAL is found at the immunological synapse and plays a crucial role in exosome secretion. However, no involvement of MAL in viral infections has been reported so far. Here, we show that herpes simplex virus 1 (HSV-1) virions travel in association with MAL-positive structures to reach the end of cellular processes, which contact uninfected oligodendrocytes. Importantly, the depletion of MAL led to a significant decrease in infection, with a drastic reduction in the number of lytic plaques in MAL-silenced cells. These results suggest a significant role for MAL in viral spread at cell contacts. The participation of MAL in the cell-to-cell spread of HSV-1 may shed light on the involvement of proteolipids in this process. IMPORTANCE Herpes simplex virus 1 (HSV-1) is a neurotropic pathogen that can infect many types of cells and establish latent infections in neurons. HSV-1 may spread from infected to uninfected cells by two main routes: by cell-free virus or by cell-to-cell spread. In the first case, virions exit into the extracellular space and then infect another cell from the outside. In the second case, viral transmission occurs through cell-to-cell contacts via a mechanism that is still poorly understood. A third mode of spread, using extracellular vesicles, also exists. In this study, we demonstrate the important role for a myelin protein, myelin and lymphocyte protein (MAL), in the process of cell-to-cell viral spread in oligodendrocytes. We show that MAL is involved in trafficking of virions along cell processes and that MAL depletion produces a significant alteration in the viral cycle, which reduces cell-to cell spread of HSV-1.

scholarly journals Induction of Rod-Shaped Structures by Herpes Simplex Virus Glycoprotein I

2020 ◽  
Vol 94 (17) ◽  
Author(s):  
Wuchao Zhang ◽  
Peng Gao ◽  
Xixi Gui ◽  
Lei Zhou ◽  
Xinna Ge ◽  
...  
Keyword(s):  
Amino Acids ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Cell Fusion ◽  
Higher Order ◽  
Order Form ◽  
Glycoprotein I ◽  
Simplex Virus ◽  
Cell Spread ◽  
Hsv 1

ABSTRACT The envelope glycoprotein I (gI) of herpes simplex virus 1 (HSV-1) is a critical mediator of virus-induced cell-to-cell spread and cell-cell fusion. Here, we report a previously unrecognized property of this molecule. In transfected cells, the HSV-1 gI was discovered to induce rod-shaped structures that were uniform in width but variable in length. Moreover, the gI within these structures was conformationally different from the typical form of gI, as a previously used monoclonal antibody mAb3104 and a newly made peptide antibody to the gI extracellular domain (ECD) (amino acids [aa] 110 to 202) both failed to stain the long rod-shaped structures, suggesting the formation of a higher-order form. Consistent with this observation, we found that gI could self-interact and that the rod-shaped structures failed to recognize glycoprotein E, the well-known binding partner of gI. Further analyses by deletion mutagenesis and construction of chimeric mutants between gI and gD revealed that the gI ECD is the critical determinant, whereas the transmembrane domain served merely as an anchor. The critical amino acids were subsequently mapped to proline residues 184 and 188 within a conserved PXXXP motif. Reverse genetics analyses showed that the ability to induce a rod-shaped structure was not required for viral replication and spread in cell culture but rather correlated positively with the capability of the virus to induce cell fusion in the UL24syn background. Together, this work discovered a novel feature of HSV-1 gI that may have important implications in understanding gI function in viral spread and pathogenesis. IMPORTANCE The HSV-1 gI is required for viral cell-to-cell spread within the host, but the molecular mechanisms of how gI exactly works have remained poorly understood. Here, we report a novel property of this molecule, namely, induction of rod-shaped structures, which appeared to represent a higher-order form of gI. We further mapped the critical residues and showed that the ability of gI to induce rod-shaped structures correlated well with the capability of HSV-1 to induce cell fusion in the UL24syn background, suggesting that the two events may have an intrinsic link. Our results shed light on the biological properties of HSV-1 gI and may have important implications in understanding viral pathogenesis.

Characterization of mutants of herpes simplex viruses, types 1 and 2, that produce fragments of the thymidine kinase polypeptide

1983 ◽  
Vol 29 (4) ◽  
pp. 385-393
Author(s):  
Timothy M. -P. Block ◽  
Nancy J. Kuhn ◽  
Karen A. Kustas ◽  
William A. Held ◽  
Kenneth Gross ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Thymidine Kinase ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
In Vitro Translation ◽  
Herpes Simplex Viruses ◽  
Simplex Virus ◽  
Hsv 1

Seven tk− mutants of herpes simplex virus, type 2 (HSV-2), and three tk− mutants of herpes simplex virus, type 1 (HSV-1), were isolated which did not produce the thymidine kinase (TK) polypeptides but formed smaller polypeptides not seen in wild-type infected cells. Positive TK mRNA selection by hybridization to the cloned tk genes followed by in vitro translation identified the TK polypeptides. Comparisons of the products of partial proteolysis of the polypeptides of four HSV-2 and two HSV-1 tk− mutants to those of the parental TK polypeptides indicated that, in each case, the novel polypeptide was a fragment of the TK polypeptide, showing that these mutants have defects in the structural gene for tk. HSV-2 mutants of this sort have not been previously described. They and the HSV-1 mutants are similar to HSV-1 mutants reported previously. In addition, it was found that TK mRNA was present early in infection but was absent late in infection, suggesting that the shutoff of TK synthesis is due to message degradation. Also, HSV-2 TK mRNA did not hybridize to the cloned HSV-1 tk gene indicating that these genes have extensively diverged.

scholarly journals Performance of Two Commercial Glycoprotein G-Based Enzyme Immunoassays for Detecting Antibodies to Herpes Simplex Viruses 1 and 2 in Children and Young Adolescents

2002 ◽  
Vol 9 (5) ◽  
pp. 1124-1125 ◽  
Author(s):  
Charles T. Leach ◽  
Rhoda L. Ashley ◽  
Jacques Baillargeon ◽  
Hal B. Jenson
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Enzyme Linked Immunosorbent Assay ◽  
Aged Patients ◽  
Herpes Simplex Viruses ◽  
Glycoprotein G ◽  
Children And Young Adolescents ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT In 61 patients 1 to 14 years of age, the Gull/Meridian enzyme-linked immunosorbent assay (ELISA) had a sensitivity of 100% for herpes simplex virus type 1 (HSV-1) and specificities of 74% for HSV-1 and 48% for HSV-2. In 128 similarly aged patients, the HerpeSelect ELISA (Focus Technologies) showed sensitivities of 80% for HSV-1 and 88% for HSV-2, and specificities of 97% for HSV-1 and 100% for HSV-2.

scholarly journals Herpes Simplex Virus type 1 infects Langerhans cells and the novel epidermal dendritic cell, Epi-cDC2s, via different entry pathways

2021 ◽  
Vol 17 (4) ◽  
pp. e1009536
Author(s):  
Kirstie M. Bertram ◽  
Naomi R. Truong ◽  
Jacinta B. Smith ◽  
Min Kim ◽  
Kerrie J. Sandgren ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Langerhans Cells ◽  
Vaccine Development ◽  
Mononuclear Phagocytes ◽  
The Novel ◽  
Endosomal Acidification ◽  
Simplex Virus ◽  
Hsv 1

Skin mononuclear phagocytes (MNPs) provide the first interactions of invading viruses with the immune system. In addition to Langerhans cells (LCs), we recently described a second epidermal MNP population, Epi-cDC2s, in human anogenital epidermis that is closely related to dermal conventional dendritic cells type 2 (cDC2) and can be preferentially infected by HIV. Here we show that in epidermal explants topically infected with herpes simplex virus (HSV-1), both LCs and Epi-cDC2s interact with HSV-1 particles and infected keratinocytes. Isolated Epi-cDC2s support higher levels of infection than LCs in vitro, inhibited by acyclovir, but both MNP subtypes express similar levels of the HSV entry receptors nectin-1 and HVEM, and show similar levels of initial uptake. Using inhibitors of endosomal acidification, actin and cholesterol, we found that HSV-1 utilises different entry pathways in each cell type. HSV-1 predominantly infects LCs, and monocyte-derived DCs, via a pH-dependent pathway. In contrast, Epi-cDC2s are mainly infected via a pH-independent pathway which may contribute to the enhanced infection of Epi-cDC2s. Both cells underwent apoptosis suggesting that Epi-cDC2s may follow the same dermal migration and uptake by dermal DCs that we have previously shown for LCs. Thus, we hypothesize that the uptake of HSV and infection of Epi-cDC2s will stimulate immune responses via a different pathway to LCs, which in future may help guide HSV vaccine development and adjuvant targeting.

Neonatal Herpes Simplex Virus Infections

1985 ◽  
Vol 7 (4) ◽  
pp. 119-126
Author(s):  
Richard J. Whitley ◽  
Cecelia Hutto
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Viral Infections ◽  
Fatal Case ◽  
Molecular Characteristics ◽  
Neonatal Herpes ◽  
Herpes Simplex Viruses ◽  
Neonatal Herpes Simplex ◽  
Simplex Virus ◽  
Hsv 1

Infections caused by herpes simplex viruses have been recognized since ancient Roman times, when Herodotus associated mouth ulcers and lip vesicles with fever. However, neonatal herpes simplex infection was not identified as a distinct disease until centuries later. Only 50 years ago, the first written descriptions of neonatal herpes were attributed nearly simultaneously to Hass, who described the histopathologic findings in a fatal case, and to Batingani who described a newborn child with herpes simplex virus (HSV) keratitis. For several decades our understanding of neonatal infections with herpes simplex virus was predicated upon histopathologic descriptions of the disease. These indicated a broad spectrum of involvement in infants. In the mid-1960s, Nahmias and Dowdle demonstrated two antigenic types of herpes simplex virus, HSV-1 and HSV-2. Recognition of these types prompted a rapid series of developments leading to a better characterization of the biochemical and molecular characteristics of the virus. One consequence of these advances has been the development of methods of typing of viruses which have been utilized to define the epidemiology of HSV infections. Herpes simplex viral infections "above-the-belt," primarily of the lip and oropharynx, have been found in most cases to be associated with HSV-1, whereas infections "below-the-belt" are usually caused by HSV-2.

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 Responses of Herpes Simplex Virus Type 1-Infected Cells to the Presence of Extracellular Antibodies: gE-Dependent Glycoprotein Capping and Enhancement in Cell-to-Cell Spread

2003 ◽  
Vol 77 (1) ◽  
pp. 701-708 ◽  
Author(s):  
Syed Monem Rizvi ◽  
Malini Raghavan
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Virus Transmission ◽  
Dependent Manner ◽  
Viral Glycoprotein ◽  
Infected Cells ◽  
Simplex Virus ◽  
Cell Spread ◽  
Hsv 1

ABSTRACT Binding of anti-herpes simplex virus (HSV) immunoglobulin G (IgG) to HSV type 1 (HSV-1)-infected HEL and HEp-2 cells causes changes in surface viral glycoprotein distribution, resulting in a capping of all viral glycoproteins towards one pole of the cell. This occurs in a gE-dependent manner. In HEL cells, low concentrations of anti-HSV IgG also enhance cell-to-cell spread of wild-type HSV-1 but not of gE deletion mutant HSV-1. These observations raised the possibility that gE-dependent mechanisms exist that allow some HSV-1-infected cells to respond to the presence of extracellular antibodies by enhancing the antibody-resistant mode of virus transmission.

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.

Sign in / Sign up

Export Citation Format

Share Document