In vitro and silico studies of geraniin interfering with HSV-2 replication by targeting glycoprotein DZhang, Cheng, Ju
Nat Prod Res (2024) 38 (12), 2053-2059
Abstract: Residues ASN94 and GLN41 presented the highest frequency in molecular docking tests. The geraniin-glycoprotein D(gD) complexes was stable with RMSD(root mean square deviation)value less than 0.3 nm. The Molecular dynamic (MD) simulations revealed stable hydrogen bonds between gD and geraniin. Root mean square fluctuation (RMSF) values were less than 0.15 nm around the interface of geraniin-gD complex. In virucidal assays showed a much higher anti-HSV-2 inhibition activity of geraniin as compared to acyclovir(ACV).Human immunodeficiency virus transactivator (HIV-TAT) treatment significantly enhanced HSV-2 replication and lethal effect on HaCaT cells. The inhibitory rate of geraniin against HSV-2 coinfected with HIV-TAT was significantly decreased. The immunofluorescence results also revealed that HSV-2 gD expression presented a green fluorescence on HaCaT cells membranes and showed clear downregulation in geraniin-treated cells, but was expressed clearly on cell membranes under geraniin, HSV-2 and HIV-TAT cotreatment. The anti-apoptotic effect from geraniin persisted after 72 h, while the anti-apoptotic effect from geraniin diminished when HIV-TAT and geraniin were combined.
A self-binding immune complex vaccine elicits strong neutralizing responses against herpes simplex virus in miceDiamos, Pardhe, Bergeman
et alFront Immunol (2023) 14, 1085911
Abstract: It has been known for over half a century that mixing an antigen with its cognate antibody in an immune complex (IC) can enhance antigen immunogenicity. However, many ICs produce inconsistent immune responses, and the use of ICs in the development new vaccines has been limited despite the otherwise widespread success of antibody-based therapeutics. To address this problem, we designed a self-binding recombinant immune complex (RIC) vaccine which mimics the larger ICs generated during natural infection.In this study, we created two novel vaccine candidates: 1) a traditional IC targeting herpes simplex virus 2 (HSV-2) by mixing glycoprotein D (gD) with a neutralizing antibody (gD-IC); and 2) an RIC consisting of gD fused to an immunoglobulin heavy chain and then tagged with its own binding site, allowing self-binding (gD-RIC). We characterized the complex size and immune receptor binding characteristics in vitro for each preparation. Then, the in vivo immunogenicity and virus neutralization of each vaccine were compared in mice.gD-RIC formed larger complexes which enhanced C1q receptor binding 25-fold compared to gD-IC. After immunization of mice, gD-RIC elicited up to 1,000-fold higher gD-specific antibody titers compared to traditional IC, reaching endpoint titers of 1:500,000 after two doses without adjuvant. The RIC construct also elicited stronger virus-specific neutralization against HSV-2, as well as stronger cross-neutralization against HSV-1, although the proportion of neutralizing antibodies to total antibodies was somewhat reduced in the RIC group.This work demonstrates that the RIC system overcomes many of the pitfalls of traditional IC, providing potent immune responses against HSV-2 gD. Based on these findings, further improvements to the RIC system are discussed. RIC have now been shown to be capable of inducing potent immune responses to a variety of viral antigens, underscoring their broad potential as a vaccine platform.Copyright © 2023 Diamos, Pardhe, Bergeman, Kamzina, DiPalma, Aman, Chaves, Lowe, Kilbourne, Hogue and Mason.
Evaluation of the antiviral potential of the soluble forms of glycoprotein D receptors on ocular herpes caused by HSV-1 and HSV-2 infections in a transgenic mouse modelFujimoto, Hikita, Takeda
et alJ Med Virol (2019) 91 (5), 820-828
Abstract: Ocular herpes, caused by herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) infections, remains an important corneal disease, which may result in loss of vision. Because the frequency of acyclovir resistance in HSV has increased, novel antiviral agents are needed for therapeutic approaches to ocular herpes. Several studies have demonstrated that fusion proteins containing entire ectodomain of HSV glycoprotein D receptors, including herpesvirus entry mediator A (HVEM), nectin-1 and nectin-2, and the Fc portion of human IgG (HVEMIg, nectin-1Ig, and nectin-2Ig, respectively), can exert antiviral effects in vitro and in vivo. Here, to evaluate the antiviral potential of HVEMIg, nectin-1Ig, and nectin-2Ig against ocular infections with HSV, transgenic mice expressing these fusion proteins were ocularly inoculated with HSV-1 and HSV-2. Transgenic mouse lines expressing HVEMIg and nectin-1Ig showed marked resistance to ocular herpes; on the other hand, mouse lines expressing nectin-2Ig did not. Furthermore, to investigate the therapeutic effects of nectin-1Ig, which can neutralize HSVs in vitro against ocular disease, transgenic mouse serum containing nectin-1Ig was dropped into the eyes of wild-type mice after HSV infection. Reduction of severe symptoms could be observed in mice treated with nectin-1Ig serum. These results warrant further study of soluble HVEM and nectin-1 products as preventive and therapeutic agents against ocular herpes caused by HSV-1 and HSV-2 infections, especially nectin-1Ig as a new eye drop.© 2018 Wiley Periodicals, Inc.
[The effect of immunization with herpes simplex virus glycoprotein D fused with interluekin-2 against murine herpetic keratitis]Inoue, Inoue, Nakamura
et alNippon Ganka Gakkai Zasshi (2001) 105 (4), 223-9
Abstract: To evaluate the effect of vaccination with fusion protein(gD-IL-2) consisting of herpes simplex type1(HSV-1) glycoprotein D(gD) and human interleukin-2(IL-2), and the effect of plasmid DNA vaccine encoding gD-IL-2 against murine herpetic keratitis.Plasmid containing gD-IL-2(pHDL-neol) was constructed, and gD-IL-2 peptide was purified. BALB/c mice were injected twice hypodermally or subconjunctivally with 1 microgram/0.1 ml of gD-IL-2 peptide, or twice subconjunctivally with 90 micrograms/0.05 ml of gD-IL-2 plasmid DNA. Neutralizing antibody titer and delayed-type hypersensitivity (DTH) against HSV-1 were measured. Immunized mice were challenged with CHR3 strain of HSV-1 via the cornea. The clinical picture of epithelial and stromal keratitis was scored.Stromal keratitis was inhibited in gD-IL-2 peptide- or gD-IL-2 DNA-immunized mice, but epithelial keratitis was not. It was confirmed that plasmid gD-IL-2 elicited significant serum virus neutralizing titer and DTH response.Vaccination with gD-IL-2 was effective against herpetic keratitis.
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