Herpes Simplex Virus Type 1 Evades the Effects of Antibody and Complement In Vivo

ABSTRACT Herpes simplex virus type 1 (HSV-1) encodes a complement-interacting glycoprotein, gC, and an immunoglobulin G (IgG) Fc binding glycoprotein, gE, that mediate immune evasion by affecting multiple aspects of innate and acquired immunity, including interfering with complement components C1q, C3, C5, and properdin and blocking antibody-dependent cellular cytotoxicity. Previous studies evaluated the individual contributions of gC and gE to immune evasion. Experiments in a murine model that examines the combined effects of gC and gE immune evasion on pathogenesis are now reported. Virulence of wild-type HSV-1 is compared with mutant viruses defective in gC-mediated C3 binding, gE-mediated IgG Fc binding, or both immune evasion activities. Eliminating both activities greatly increased susceptibility of HSV-1 to antibody and complement neutralization in vitro and markedly reduced virulence in vivo as measured by disease scores, virus titers, and mortality. Studies with C3 knockout mice indicated that other activities attributed to these glycoproteins, such as gC-mediated virus attachment to heparan sulfate or gE-mediated cell-to-cell spread, do not account for the reduced virulence of mutant viruses. The results support the importance of gC and gE immune evasion in vivo and suggest potential new targets for prevention and treatment of HSV disease.

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Antiviral effect of oryzacystatin, a proteinase inhibitor in rice, against herpes simplex virus type 1 in vitro and in vivo.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.39.4.846 ◽

1995 ◽

Vol 39 (4) ◽

pp. 846-849 ◽

Cited By ~ 41

Author(s):

H Aoki ◽

T Akaike ◽

K Abe ◽

M Kuroda ◽

S Arai ◽

...

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

Virus Type ◽

Herpes Simplex Virus Type ◽

Rice Seed ◽

Simplex Virus ◽

Hsv 1

Oryzacystatin (OC) is the first-described cystatin originating from rice seed; it consists of two molecular species, OC-I and OC-II, which have antiviral action against poliovirus in vitro (H. Kondo, S. Ijiri, K. Abe, H. Maeda, and S. Arai, FEBS Lett. 299:48-50, 1992). In the experiments reported here, we investigated the effects of OC-I and OC-II on the replication of herpes simplex virus type 1 (HSV-1) in vitro and in vivo. HSV-1 was inoculated onto monolayers of monkey kidney epithelial cells (CV-1 cells) at a multiplicity of infection of 0.1 PFU per cell. After adsorption of the virus onto cells, the cultures were incubated in the presence of either OC-I or OC-II in the concentration range of 1.0 to 300 microM, and the supernatant virus yield was quantitated at 24 h. The effective concentration for 90% inhibition of HSV-1 was 14.8 microM, while a cytotoxic effect on CV-1 cells without infection of HSV-1 was not observed below 500 microM OC-I. Therefore, the apparent in vitro chemotherapeutic index was estimated to be more than 33. In the mouse model of HSV-1-induced keratitis and encephalopathy, topical administration of OC-I to the mouse cornea produced a significant decrease in virus production in the cornea (mean virus yields: 3.11 log10 PFU in the treated group and 4.37 log10 PFU in the control group) and significant improvement in survival rates (P = 0.01). The in vivo antiherpetic effect of OC-I was comparable to that of acyclovir, indicating that topical treatment of HSV-1 infection in humans with OC-I might be possible. Our data also suggest the importance of some thiol proteinases, which may be derived from either the host's cells or HSV-1, during the replication process of HSV-1.

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In Vivo Ablation of CD11c-Positive Dendritic Cells Increases Susceptibility to Herpes Simplex Virus Type 1 Infection and Diminishes NK and T-Cell Responses

Journal of Virology ◽

10.1128/jvi.80.8.3985-3993.2006 ◽

2006 ◽

Vol 80 (8) ◽

pp. 3985-3993 ◽

Cited By ~ 91

Author(s):

Sadik H. Kassim ◽

Naveen K. Rajasagi ◽

Xiangyi Zhao ◽

Robert Chervenak ◽

Stephen R. Jennings

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

T Cell ◽

Virus Type ◽

Herpes Simplex Virus Type ◽

Simplex Virus ◽

Hsv 1

ABSTRACT The precise role of each of the seven individual CD11c+ dendritic cell subsets (DCs) identified to date in the response to viral infections is not known. DCs serve as critical links between the innate and adaptive immune responses against many pathogens, including herpes simplex virus type 1 (HSV-1). The role of DCs as mediators of resistance to HSV-1 infection was investigated using CD11c-diphtheria toxin (DT) receptor-green fluorescent protein transgenic mice, in which DCs can be transiently depleted in vivo by treatment with low doses of DT. We show that ablation of DCs led to enhanced susceptibility to HSV-1 infection in the highly resistant C57BL/6 mouse strain. Specifically, we showed that the depletion of DCs led to increased viral spread into the nervous system, resulting in an increased rate of morbidity and mortality. Furthermore, we showed that ablation of DCs impaired the optimal activation of NK cells and CD4+ and CD8+ T cells in response to HSV-1. These data demonstrated that DCs were essential not only in the optimal activation of the acquired T-cell response to HSV-1 but also that DCs were crucial for innate resistance to HSV-1 infection.

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Blocking Antibody Access to Neutralizing Domains on Glycoproteins Involved in Entry as a Novel Mechanism of Immune Evasion by Herpes Simplex Virus Type 1 Glycoproteins C and E

Journal of Virology ◽

10.1128/jvi.02599-07 ◽

2008 ◽

Vol 82 (14) ◽

pp. 6935-6941 ◽

Cited By ~ 22

Author(s):

Lauren M. Hook ◽

Jialing Huang ◽

Ming Jiang ◽

Richard Hodinka ◽

Harvey M. Friedman

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

Virus Type ◽

Immune Evasion ◽

Herpes Simplex Virus Type ◽

Mutant Virus ◽

Antibody Neutralization ◽

Simplex Virus ◽

Hsv 1

ABSTRACT Herpes simplex virus type 1 (HSV-1) glycoprotein C (gC) blocks complement activation, and glycoprotein E (gE) interferes with IgG Fc-mediated activities. While evaluating gC- and gE-mediated immune evasion in human immunodeficiency virus (HIV)-HSV-1-coinfected subjects, we noted that antibody alone was more effective at neutralizing a strain with mutations in gC and gE (gC/gE) than a wild-type (WT) virus. This result was unexpected since gC and gE are postulated to interfere with complement-mediated neutralization. We used pooled human immunoglobulin G (IgG) from HIV-negative donors to confirm the results and evaluated mechanisms of the enhanced antibody neutralization. We demonstrated that differences in antibody neutralization cannot be attributed to the concentrations of HSV-1 glycoproteins on the two viruses or to the absence of an IgG Fc receptor on the gC/gE mutant virus or to enhanced neutralization of the mutant virus by antibodies that target only gB, gD, or gH/gL, which are the glycoproteins involved in virus entry. Since sera from HIV-infected subjects and pooled human IgG contain antibodies against multiple glycoproteins, we determined whether differences in neutralization become apparent when antibodies to gB, gD, or gH/gL are used in combination. Neutralization of the gC/gE mutant was greatly increased compared that of WT virus when any two of the antibodies against gB, gD, or gH/gL were used in combination. These results suggest that gC and gE on WT virus provide a shield against neutralizing antibodies that interfere with gB-gD, gB-gH/gL, or gD-gH/gL interactions and that one function of virus neutralization is to prevent interactions between these glycoproteins.

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Herpes Simplex Virus Type 1 Glycoprotein gC Mediates Immune Evasion In Vivo

Journal of Virology ◽

10.1128/jvi.72.10.8257-8263.1998 ◽

1998 ◽

Vol 72 (10) ◽

pp. 8257-8263 ◽

Cited By ~ 71

Author(s):

John M. Lubinski ◽

Liyang Wang ◽

Athena M. Soulika ◽

Reinhard Burger ◽

Rick A. Wetsel ◽

...

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

Virus Type ◽

Immune Evasion ◽

Herpes Simplex Virus Type ◽

Guinea Pigs ◽

Wild Type ◽

Simplex Virus

ABSTRACT Many microorganisms encode proteins that interact with molecules involved in host immunity; however, few of these molecules have been proven to promote immune evasion in vivo. Herpes simplex virus type 1 (HSV-1) glycoprotein C (gC) binds complement component C3 and inhibits complement-mediated virus neutralization and lysis of infected cells in vitro. To investigate the importance of the interaction between gC and C3 in vivo, we studied the virulence of a gC-null strain in complement-intact and C3-deficient animals. Using a vaginal infection model in complement-intact guinea pigs, we showed that gC-null virus grows to lower titers and produces less severe vaginitis than wild-type or gC rescued virus, indicating a role for gC in virulence. To determine the importance of complement, studies were performed with C3-deficient guinea pigs; the results demonstrated significant increases in vaginal titers of gC-null virus, while wild-type and gC rescued viruses showed nonsignificant changes in titers. Similar findings were observed for mice where gC null virus produced significantly less disease than gC rescued virus at the skin inoculation site. Proof that C3 is important was provided by studies of C3 knockout mice, where disease scores of gC-null virus were significantly higher than in complement-intact mice. The results indicate that gC-null virus is approximately 100-fold (2 log10) less virulent that wild-type virus in animals and that gC-C3 interactions are involved in pathogenesis.

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The latency-associated transcript gene of herpes simplex virus type 1 (HSV-1) is required for efficient in vivo spontaneous reactivation of HSV-1 from latency.

Journal of Virology ◽

10.1128/jvi.68.12.8045-8055.1994 ◽

1994 ◽

Vol 68 (12) ◽

pp. 8045-8055 ◽

Cited By ~ 161

Author(s):

G C Perng ◽

E C Dunkel ◽

P A Geary ◽

S M Slanina ◽

H Ghiasi ◽

...

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

Virus Type ◽

Herpes Simplex Virus Type ◽

Simplex Virus ◽

Transcript Gene ◽

Spontaneous Reactivation ◽

Hsv 1

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Sodium Butyrate: a Chemical Inducer of In Vivo Reactivation of Herpes Simplex Virus Type 1 in the Ocular Mouse Model

Journal of Virology ◽

10.1128/jvi.00070-07 ◽

2007 ◽

Vol 81 (11) ◽

pp. 6106-6110 ◽

Cited By ~ 23

Author(s):

Donna M. Neumann ◽

Partha S. Bhattacharjee ◽

James M. Hill

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

Virus Type ◽

Sodium Butyrate ◽

Herpes Simplex Virus Type ◽

Early Time ◽

Simplex Virus ◽

Hsv 1

ABSTRACT Recent studies have explored the chromatin structures associated with the herpes simplex virus type 1 (HSV-1) genome during latency, particularly with regard to specific histone tail modifications such as acetylation and dimethylation. The objective of our present study was to develop a rapid systemic method of in vivo HSV-1 reactivation to further explore the changes that occur in the chromatin structures associated with HSV-1 at early time points after the initiation of HSV reactivation. We present a uniform, rapid, and reliable method of in vivo HSV-1 reactivation in mice that yields high reactivation frequencies (75 to 100%) by using sodium butyrate, a histone deacetylase inhibitor, and demonstrate that the reactivating virus can be detected at the original site of infection.

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Immunization Strategies To Block the Herpes Simplex Virus Type 1 Immunoglobulin G Fc Receptor

Journal of Virology ◽

10.1128/jvi.78.5.2562-2571.2004 ◽

2004 ◽

Vol 78 (5) ◽

pp. 2562-2571 ◽

Cited By ~ 19

Author(s):

Xiaoqing Lin ◽

John M. Lubinski ◽

Harvey M. Friedman

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

Virus Type ◽

Immune Evasion ◽

Immunoglobulin G ◽

Herpes Simplex Virus Type ◽

Fc Receptor ◽

Simplex Virus ◽

Hsv 1

ABSTRACT Herpes simplex virus type 1 (HSV-1) glycoprotein gE functions as an immunoglobulin G (IgG) Fc receptor (FcγR) that promotes immune evasion. When an IgG antibody binds by the F(ab′)2 domain to an HSV antigen, the Fc domain of some of the same antibody molecules binds to the FcγR, which blocks Fc-mediated functions. gE is a type 1 membrane glycoprotein with a large ectodomain that is expressed on the virion envelope and infected-cell surface. Our goal was to determine if immunizing with gE protein fragments could produce antibodies that bind by the F(ab′)2 domain to gE and block the FcγR, as measured by competitively inhibiting nonimmune human IgG binding to the FcγR. Three gE peptides were constructed in baculovirus spanning almost the entire ectodomain and used to immunize mice and rabbits. Two fragments were highly effective at producing antibodies that bind by the F(ab′)2 domain and block the FcγR. The most potent of these two antibodies was far more effective at blocking the FcγR than antibodies that are only capable of binding by the Fc domains to the FcγR, including anti-gC, anti-gD, and nonimmune IgG. These results suggest that immunizing with gE fragments has potential for preventing immune evasion by blocking activities mediated by the HSV-1 FcγR.

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Evaluation of a peptidomimetic ribonucleotide reductase inhibitor with a murine model of herpes simplex virus type 1 ocular disease.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.40.5.1078 ◽

1996 ◽

Vol 40 (5) ◽

pp. 1078-1084 ◽

Cited By ~ 18

Author(s):

C R Brandt ◽

B Spencer ◽

P Imesch ◽

M Garneau ◽

R Déziel

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

Virus Type ◽

Ribonucleotide Reductase ◽

Herpes Simplex Virus Type ◽

Ocular Infection ◽

Simplex Virus ◽

Hsv 1

The ribonucleotide reductase (RR) of herpes simplex virus type 1 (HSV-1) is an important virulence factor, being required for neurovirulence, ocular virulence, and reactivation from latency. The RR activity requires the association of two distinct homodimeric subunits, and the association of the subunits is inhibited in the presence of a peptide homologous to the carboxy terminus of the small subunit. A structural analog of the inhibitory peptide (BILD 1263) has been shown to inhibit the replication of HSV-1 at micromolar concentrations in vitro. We used a mouse model of HSV-1 ocular infection to determine the in vivo efficacy of topical BILD 1263. Treatment of HSV-1 KOS-infected mice resulted in significant reductions in the severity and incidence of stromal keratitis and corneal neovascularization. At higher concentrations (5%) BILD 1263 reduced the severity but not the incidence of blepharitis. Treatment with 5% BILD 1263 also reduced viral shedding from the cornea by 10- to 14-fold (P < 0.001). In uninfected mice treated with 5% BILD 1263, we found no evidence of corneal epithelial damage, conjunctivitis, or blepharitis, and histopathological studies revealed no changes in the corneas of these mice. These results show that the peptidomimetic RR inhibitor BILD 1263 is effective in preventing disease, has an antiviral effect in vivo, and has little or no toxicity.

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