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Nabi R, Chouljenko VN, Musarrat F, Davis ME, Mohan H, Ghavimi R, Stanfield B, Dutta O, Kousoulas KG. The Novel Oncolytic Herpes Simplex Virus Type-1 (HSV-1) Vaccine Strain VC2 Constitutively Expressing GM-CSF Causes Increased Intratumoral T Cell Infiltration and Inhibition of Tumor Metastasis in the 4T1/Balb/c Mouse Model of Stage Four Breast Cancer. J Med Virol 2025; 97:e70220. [PMID: 39930884 DOI: 10.1002/jmv.70220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 01/24/2025] [Accepted: 01/26/2025] [Indexed: 05/08/2025]
Abstract
Oncolytic virotherapy (OVT) aims to disrupt the tumor microenvironment and provide a unique therapeutic approach against solid tumors. Herpes simplex virus type-1 (HSV-1) has shown strong promise for treating various solid tumors and has been approved to treat melanoma and glioma in human patients. Previously, we reported the generation of an engineered HSV-1 vaccine strain VC2, which has shown exceptional promise as an oncolytic and immunotherapeutic virus. In the present work, we engineered VC2 to constitutively express the murine granulocyte-macrophage colony-stimulating factor (GM-CSF) gene inserted in place of HSV-1 Glycoprotein C (gC). We tested the efficacy of VC2-GMCSF for its ability to generate antitumor response in the 4T1 stage four metastatic breast cancer mouse model. GM-CSF expression enhanced VC2 viral replication and infectious virus production. Tumors formed after 7 days of engraftment in the mammary fat pad of Balb/CJ mice were treated by injecting ~5 × 104 plaque forming units (PFU) of VC2/VC2-GMCSF once. Intratumor treatment did not appreciably reduce average primary tumor sizes. However, metastatic foci were significantly reduced in mice lungs treated with VC2-GMCSF compared to VC2 or mock treatment. VC2-GMCSF intratumoral treatment induced a stronger intratumor T cell infiltration but not an increased cytotoxic activity. A significant T cell infiltration was observed in the metastatic areas in VC2-GMCSF treated animals, which was associated with reduced pro-tumor marker PDL1 and VEGF gene expression. These results show that constitutive expression of GM-CSF enhanced the overall efficacy of VC2 for OVT. VC2-GMCSF holds promise as oncolytic and immunotherapeutic virotherapy for breast and other cancers.
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Affiliation(s)
- Rafiq Nabi
- Department of Pathobiological Sciences, Louisiana State University School of Veterinary Medicine, Baton Rouge, Louisiana, USA
- Division of Biotechnology and Molecular Medicine, School of Veterinary Medicine, Baton Rouge, Louisiana, USA
| | - Vladimir N Chouljenko
- Department of Pathobiological Sciences, Louisiana State University School of Veterinary Medicine, Baton Rouge, Louisiana, USA
- Division of Biotechnology and Molecular Medicine, School of Veterinary Medicine, Baton Rouge, Louisiana, USA
| | - Farhana Musarrat
- Department of Pathobiological Sciences, Louisiana State University School of Veterinary Medicine, Baton Rouge, Louisiana, USA
- Division of Biotechnology and Molecular Medicine, School of Veterinary Medicine, Baton Rouge, Louisiana, USA
| | - Megan E Davis
- Department of Pathobiological Sciences, Louisiana State University School of Veterinary Medicine, Baton Rouge, Louisiana, USA
| | - Harikrishnan Mohan
- Department of Pathobiological Sciences, Louisiana State University School of Veterinary Medicine, Baton Rouge, Louisiana, USA
- Division of Biotechnology and Molecular Medicine, School of Veterinary Medicine, Baton Rouge, Louisiana, USA
| | - Reza Ghavimi
- Department of Pathobiological Sciences, Louisiana State University School of Veterinary Medicine, Baton Rouge, Louisiana, USA
- Division of Biotechnology and Molecular Medicine, School of Veterinary Medicine, Baton Rouge, Louisiana, USA
| | - Brent Stanfield
- Department of Pathobiological Sciences, Louisiana State University School of Veterinary Medicine, Baton Rouge, Louisiana, USA
| | - Ojasvi Dutta
- Department of Pathobiological Sciences, Louisiana State University School of Veterinary Medicine, Baton Rouge, Louisiana, USA
- Division of Biotechnology and Molecular Medicine, School of Veterinary Medicine, Baton Rouge, Louisiana, USA
| | - Konstantin G Kousoulas
- Department of Pathobiological Sciences, Louisiana State University School of Veterinary Medicine, Baton Rouge, Louisiana, USA
- Division of Biotechnology and Molecular Medicine, School of Veterinary Medicine, Baton Rouge, Louisiana, USA
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Sohrabi R, Miri AH, Rad-Malekshahi M, Saadatpour F, Pourjabbar B, Keshel SH, Arefian E, Balalaei S, Masoumi A, Khalili F, Haririan I, Akrami M, Shahriari MH. Development of silk fibroin/collagen film containing GI-20 peptide-loaded PLGA nanoparticles against corneal herpes simplex virus-1. Int J Pharm 2025; 669:125022. [PMID: 39674383 DOI: 10.1016/j.ijpharm.2024.125022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Revised: 11/27/2024] [Accepted: 11/30/2024] [Indexed: 12/16/2024]
Abstract
Herpes simplex virus-1 (HSV-1) is the primary cause of infectious blindness. Despite impressive therapeutic outcomes of conventional treatments, HSV-1 drug resistance can be easily developed. Thus, more constructive strategies should be implemented. Led by this inspiration, this work describes the potential utility of a biodegradable silk fibroin/collagen (SF/Col) film combined with GI-20-loaded poly lactic-co-glycolic acid (PLGA) nanoparticle to provide efficient and sustained delivery platform for synthetic GI-20 peptide against HSV-1. A non-irritant film containing 90 % SF and 10 % Col incorporated with mentioned nanodrug showed some optimum physicochemical properties including loading efficiency (74.15 % ± 1.12), tensile strength (3.16 ± 0.67 MPa), water uptake ability (∼73 %), cytocompatibility (viable up to 35 µg/mL of GI-20), and sustained release paradigm (∼90 % within 14 days). Also, GI-20 peptide at concentration of 35 µg/mL could prophylactically attenuate viral titration by 5 log10 units. In addition, the corneal uptake was improved without vascular irritation. In accordance with in vitro results, no hallmarks of keratitis and significant neovascularization along with ignorable inflammatory responses were obtained. Taken together, these results could guarantee the potential of mentioned multifunctional biomaterial in the healing of infected corneal tissue.
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Affiliation(s)
- Razieh Sohrabi
- Department of Pharmaceutical Biomaterials and Medical Biomaterials Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Amir Hossein Miri
- Department of Pharmaceutical Biomaterials and Medical Biomaterials Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Mazda Rad-Malekshahi
- Department of Pharmaceutical Biomaterials and Medical Biomaterials Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Saadatpour
- Molecular Virology Lab, Department of Microbiology, School of Biology, College of Science, University of Tehran, Tehran, Iran
| | - Bahareh Pourjabbar
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Saeed Heidari Keshel
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Medical Nanotechnology and Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ehsan Arefian
- Department of Microbiology, School of Biology, College of Science, University of Tehran, Tehran, Iran; Pediatric Cell and Gene Therapy Research Center, Gene, Cell & Tissue Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Saeed Balalaei
- Peptide Chemistry Research Center, K. N. Toosi University of Technology, Tehran, Iran
| | - Ahmad Masoumi
- Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Science, Tehran, Iran
| | - Fereshte Khalili
- Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Ismaeil Haririan
- Department of Pharmaceutical Biomaterials and Medical Biomaterials Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
| | - Mohammad Akrami
- Department of Pharmaceutical Biomaterials and Medical Biomaterials Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
| | - Mohammad Hassan Shahriari
- Department of Biotechnology Engineering, School of Chemical Engineering, College of Engineering, University of Tehran, Tehran, Iran
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Musa M, Bale BI, Suleman A, Aluyi-Osa G, Chukwuyem E, D’Esposito F, Gagliano C, Longo A, Russo A, Zeppieri M. Possible viral agents to consider in the differential diagnosis of blepharoconjunctivitis. World J Virol 2024; 13:97867. [PMID: 39722756 PMCID: PMC11551683 DOI: 10.5501/wjv.v13.i4.97867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 08/20/2024] [Accepted: 08/27/2024] [Indexed: 10/18/2024] Open
Abstract
BACKGROUND Blepharoconjunctivitis poses a diagnostic challenge due to its diverse etiology, including viral infections. Blepharoconjunctivits can be acute or chronic, self-limiting, or needing medical therapy. AIM To review possible viral agents crucial for accurate differential diagnosis in cases of blepharoconjunctivitis. METHODS The PubMed database was searched for records relating to viral blepharoconjunctivitis. The search string generated was "("virally"[All Fields] OR "virals"[All Fields] OR "virology"[MeSH Terms] OR "virology"[All Fields] OR "viral"[All Fields]) AND "Blepharoconjunctivitis"[All Fields]". RESULTS A total of 24 publications were generated from the search string. Reference lists from each relevant article were also searched for more information and included in this review. Viral etiologies such as adenovirus, herpes simplex virus (HSV), varicella-zoster virus (VZV), and Epstein-Barr virus (EBV) are frequently implicated. Adenoviral infections manifest with follicular conjunctivitis and preauricular lymphadenopathy, often presenting as epidemic keratoconjunctivitis. HSV and VZV infections can result in herpetic keratitis and may exhibit characteristic dendritic corneal ulcers. EBV, although less common, can cause unilateral or bilateral follicular conjunctivitis, particularly in immunocompromised individuals. Other potential viral agents, such as enteroviruses and molluscum contagiosum virus, should also be considered, especially in pediatric cases. CONCLUSION Prompt recognition of these viral etiologies is essential for appropriate management and prevention of complications. Thus, a thorough understanding of the clinical presentation, epidemiology, and diagnostic modalities is crucial for accurate identification and management of viral blepharoconjunctivitis.
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Affiliation(s)
- Mutali Musa
- Department of Optometry, University of Benin, Benin 300283, Nigeria
- Department of Ophthalmology, Africa Eye Laser Centre Ltd, Benin 300105, Nigeria
- Department of Ophthalmology, Centre for Sight Africa Ltd, Nkpor 434212, Nigeria
| | | | - Ayuba Suleman
- Department of Ophthalmology, Africa Eye Laser Centre Ltd, Benin 300105, Nigeria
| | - Gladness Aluyi-Osa
- Department of Ophthalmology, Africa Eye Laser Centre Ltd, Benin 300105, Nigeria
| | - Ekele Chukwuyem
- Department of Ophthalmology, Centre for Sight Africa Ltd, Nkpor 434212, Nigeria
| | - Fabiana D’Esposito
- Imperial College Ophthalmic Research Group Unit, Imperial College, London NW1 5QH, United Kingdom
- GENOFTA srl, Via A. Balsamo, 93, Naples 80065, Italy
| | - Caterina Gagliano
- Department of Medicine and Surgery, University of Enna "Kore", Catania 94100, Italy
- Eye Clinic, Catania University San Marco Hospital, Catania 95121, Italy
| | - Antonio Longo
- Department of Ophthalmology, University Hospital of Catania, Catania 95123, Italy
| | - Andrea Russo
- Department of Ophthalmology, University Hospital of Catania, Catania 95123, Italy
| | - Marco Zeppieri
- Department of Ophthalmology, University Hospital of Udine, Udine 33100, Italy
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Su D, Han L, Shi C, Li Y, Qian S, Feng Z, Yu L. An updated review of HSV-1 infection-associated diseases and treatment, vaccine development, and vector therapy application. Virulence 2024; 15:2425744. [PMID: 39508503 PMCID: PMC11562918 DOI: 10.1080/21505594.2024.2425744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Revised: 09/24/2024] [Accepted: 10/31/2024] [Indexed: 11/15/2024] Open
Abstract
Herpes simplex virus type 1 (HSV-1) is a globally widespread virus that causes and associates with a wide range of diseases, including herpes simplex encephalitis, herpes simplex keratitis, and herpes labialis. The interaction between HSV-1 and the host involves complex immune response mechanisms, including recognition of viral invasion, maintenance of latent infection, and triggering of reactivation. Antiviral therapy is the core treatment for HSV-1 infections. Meanwhile, vaccine development employs different strategies and methods, and several promising vaccine types have emerged, such as live attenuated, protein subunit, and nucleic acid vaccines, offering new possibilities for the prevention of HSV-1 infection. Moreover, HSV-1 can be modified into a therapeutic vector for gene therapy and tumour immunotherapy. This review provides an in-depth summary of HSV-1 infection-associated innate and adaptive immune responses, disease pathogenesis, current therapeutic approaches, recent advances in vaccine development, and vector therapy applications for cancer treatment. Through a systematic review of multiple aspects of HSV-1, this study aims to provide a comprehensive and detailed reference for the public on the prevention, control, and treatment of HSV-1.
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Affiliation(s)
- Dan Su
- Department of Endocrine, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang Medical University, Xinxiang, Henan, China
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, China
- Xinxiang Engineering Technology Research Center of Immune Checkpoint Drug for Liver-Intestinal Tumors, Xinxiang Medical University, Xinxiang, Henan, P.R.China
| | - Liping Han
- Department of Endocrine, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang Medical University, Xinxiang, Henan, China
| | - Chengyu Shi
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, China
- Xinxiang Engineering Technology Research Center of Immune Checkpoint Drug for Liver-Intestinal Tumors, Xinxiang Medical University, Xinxiang, Henan, P.R.China
| | - Yaoxin Li
- Department of Endocrine, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang Medical University, Xinxiang, Henan, China
- Xinxiang Engineering Technology Research Center of Immune Checkpoint Drug for Liver-Intestinal Tumors, Xinxiang Medical University, Xinxiang, Henan, P.R.China
| | - Shaoju Qian
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, China
- Xinxiang Engineering Technology Research Center of Immune Checkpoint Drug for Liver-Intestinal Tumors, Xinxiang Medical University, Xinxiang, Henan, P.R.China
| | - Zhiwei Feng
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, China
- Xinxiang Engineering Technology Research Center of Immune Checkpoint Drug for Liver-Intestinal Tumors, Xinxiang Medical University, Xinxiang, Henan, P.R.China
| | - Lili Yu
- Department of Endocrine, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang Medical University, Xinxiang, Henan, China
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, China
- Xinxiang Engineering Technology Research Center of Immune Checkpoint Drug for Liver-Intestinal Tumors, Xinxiang Medical University, Xinxiang, Henan, P.R.China
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Rider PJF, Dulin H, Uche IK, McGee MC, Huang W, Kousoulas KG, Hai R. A Herpes Simplex Virus Type-1-Derived Influenza Vaccine Induces Balanced Adaptive Immune Responses and Protects Mice From Lethal Influenza Virus Challenge. J Med Virol 2024; 96:e70067. [PMID: 39568407 DOI: 10.1002/jmv.70067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 10/29/2024] [Accepted: 10/31/2024] [Indexed: 11/22/2024]
Abstract
Influenza virus is a major respiratory viral pathogen responsible for the deaths of hundreds of thousands worldwide each year. Current vaccines provide protection primarily by inducing strain-specific antibody responses with the requirement of a match between vaccine strains and circulating strains. It has been suggested that anti-influenza T-cell responses, in addition to antibody responses may provide the broadest protection against different flu strains. Therefore, to address this urgent need, it is desirable to develop a vaccine candidate with an ability to induce balanced adaptive immunity including cell mediated immune responses. Here, we explored the potential of VC2, a well-characterized Herpes Simplex Virus type 1 vaccine vector, as a live attenuated influenza vaccine candidate. We generated a recombinant VC2 virus expressing the influenza A hemagglutinin protein. We show that this virus is capable of generating potent and specific anti-influenza humoral and cell-mediated immune responses. We further show that a single vaccination with the VC2-derived influenza vaccine protects mice from lethal challenge with influenza virus. Our data support the continued development of VC2-derived influenza vaccines for protection of human populations from both seasonal and pandemic strains of influenza. Finally, our results support the potential of VC2-derived vaccines as a platform for the rapid development of vaccines against emerging and established pathogens, particularly respiratory pathogens.
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MESH Headings
- Animals
- Influenza Vaccines/immunology
- Influenza Vaccines/administration & dosage
- Adaptive Immunity
- Antibodies, Viral/blood
- Antibodies, Viral/immunology
- Mice
- Orthomyxoviridae Infections/prevention & control
- Orthomyxoviridae Infections/immunology
- Herpesvirus 1, Human/immunology
- Herpesvirus 1, Human/genetics
- Vaccines, Attenuated/immunology
- Vaccines, Attenuated/administration & dosage
- Mice, Inbred BALB C
- Female
- Hemagglutinin Glycoproteins, Influenza Virus/immunology
- Hemagglutinin Glycoproteins, Influenza Virus/genetics
- Vaccines, Synthetic/immunology
- Vaccines, Synthetic/administration & dosage
- Vaccines, Synthetic/genetics
- Immunity, Cellular
- Disease Models, Animal
- Humans
- Survival Analysis
- Genetic Vectors/immunology
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Affiliation(s)
- Paul J F Rider
- Division of Biotechnology and Molecular Medicine Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana, USA
- Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana, USA
| | - Harrison Dulin
- Department of Microbiology and Plant Pathology, University of California, Riverside, California, USA
| | - Ifeanyi K Uche
- Division of Biotechnology and Molecular Medicine Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana, USA
- Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana, USA
| | - Michael C McGee
- Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana, USA
| | - Weishan Huang
- Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana, USA
- Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York, USA
| | - Konstantin G Kousoulas
- Division of Biotechnology and Molecular Medicine Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana, USA
- Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana, USA
| | - Rong Hai
- Department of Microbiology and Plant Pathology, University of California, Riverside, California, USA
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Bloom DC, Lilly C, Canty W, Vilaboa N, Voellmy R. Very Broadly Effective Hemagglutinin-Directed Influenza Vaccines with Anti-Herpetic Activity. Vaccines (Basel) 2024; 12:537. [PMID: 38793788 PMCID: PMC11125745 DOI: 10.3390/vaccines12050537] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 05/08/2024] [Accepted: 05/11/2024] [Indexed: 05/26/2024] Open
Abstract
A universal vaccine that generally prevents influenza virus infection and/or illness remains elusive. We have been exploring a novel approach to vaccination involving replication-competent controlled herpesviruses (RCCVs) that can be deliberately activated to replicate efficiently but only transiently in an administration site in the skin of a subject. The RCCVs are derived from a virulent wild-type herpesvirus strain that has been engineered to contain a heat shock promoter-based gene switch that controls the expression of, typically, two replication-essential viral genes. Additional safety against inadvertent replication is provided by an appropriate secondary mechanism. Our first-generation RCCVs can be activated at the administration site by a mild local heat treatment in the presence of an antiprogestin. Here, we report that epidermal vaccination with such RCCVs expressing a hemagglutinin or neuraminidase of an H1N1 influenza virus strain protected mice against lethal challenges by H1N1 virus strains representing 75 years of evolution. Moreover, immunization with an RCCV expressing a subtype H1 hemagglutinin afforded full protection against a lethal challenge by an H3N2 influenza strain, and an RCCV expressing a subtype H3 hemagglutinin protected against a lethal challenge by an H1N1 strain. Vaccinated animals continued to gain weight normally after the challenge. Protective effects were even observed in a lethal influenza B virus challenge. The RCCV-based vaccines induced robust titers of in-group, cross-group and even cross-type neutralizing antibodies. Passive immunization suggested that observed vaccine effects were at least partially antibody-mediated. In summary, RCCVs expressing a hemagglutinin induce robust and very broad cross-protective immunity against influenza.
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Affiliation(s)
- David C. Bloom
- Department of Molecular Genetics & Microbiology, University of Florida College of Medicine, Gainesville, FL 32610-0266, USA; (D.C.B.); (C.L.); (W.C.)
| | - Cameron Lilly
- Department of Molecular Genetics & Microbiology, University of Florida College of Medicine, Gainesville, FL 32610-0266, USA; (D.C.B.); (C.L.); (W.C.)
| | - William Canty
- Department of Molecular Genetics & Microbiology, University of Florida College of Medicine, Gainesville, FL 32610-0266, USA; (D.C.B.); (C.L.); (W.C.)
| | - Nuria Vilaboa
- Hospital Universitario La Paz-IdiPAZ, 28046 Madrid, Spain;
- CIBER de Bioingenieria, Biomateriales y Nanomedicina, CIBER de Bioingenieria, Biomateriales y Nanomedicina, 28046 Madrid, Spain
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Musa M, Enaholo E, Aluyi-Osa G, Atuanya GN, Spadea L, Salati C, Zeppieri M. Herpes simplex keratitis: A brief clinical overview. World J Virol 2024; 13:89934. [PMID: 38616855 PMCID: PMC11008405 DOI: 10.5501/wjv.v13.i1.89934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Revised: 12/28/2023] [Accepted: 01/22/2024] [Indexed: 03/11/2024] Open
Abstract
The aim of our minireview is to provide a brief overview of the diagnosis, clinical aspects, treatment options, management, and current literature available regarding herpes simplex keratitis (HSK). This type of corneal viral infection is caused by the herpes simplex virus (HSV), which can affect several tissues, including the cornea. One significant aspect of HSK is its potential to cause recurrent episodes of inflammation and damage to the cornea. After the initial infection, the HSV can establish a latent infection in the trigeminal ganglion, a nerve cluster near the eye. The virus may remain dormant for extended periods. Periodic reactivation of the virus can occur, leading to recurrent episodes of HSK. Factors triggering reactivation include stress, illness, immunosuppression, or trauma. Recurrent episodes can manifest in different clinical patterns, ranging from mild epithelial involvement to more severe stromal or endothelial disease. The severity and frequency of recurrences vary among individuals. Severe cases of HSK, especially those involving the stroma and leading to scarring, can result in vision impairment or even blindness in extreme cases. The cornea's clarity is crucial for good vision, and scarring can compromise this, potentially leading to visual impairment. The management of HSK involves not only treating acute episodes but also implementing long-term strategies to prevent recurrences and attempt repairs of corneal nerve endings via neurotization. Antiviral medications, such as oral Acyclovir or topical Ganciclovir, may be prescribed for prophylaxis. The immune response to the virus can contribute to corneal damage. Inflammation, caused by the body's attempt to control the infection, may inadvertently harm the corneal tissues. Clinicians should be informed about triggers and advised on measures to minimize the risk of reactivation. In summary, the recurrent nature of HSK underscores the importance of both acute and long-term management strategies to preserve corneal health and maintain optimal visual function.
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Affiliation(s)
- Mutali Musa
- Department of Optometry, University of Benin, Benin 300283, Nigeria
- Department of Ophthalmology, Africa Eye Laser Centre, Km 7, Benin 300105, Nigeria
| | - Ehimare Enaholo
- Department of Ophthalmology, Africa Eye Laser Centre, Km 7, Benin 300105, Nigeria
- Department of Ophthalmology, Centre for Sight Africa, Nkpor 434101, Nigeria
| | - Gladness Aluyi-Osa
- Department of Ophthalmology, Africa Eye Laser Centre, Km 7, Benin 300105, Nigeria
| | | | - Leopoldo Spadea
- Eye Clinic, Policlinico Umberto I, "Sapienza" University of Rome, Rome 00142, Italy
| | - Carlo Salati
- Department of Ophthalmology, University Hospital of Udine, Udine 33100, Italy
| | - Marco Zeppieri
- Department of Ophthalmology, University Hospital of Udine, Udine 33100, Italy
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8
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Nabi R, Musarrat F, Menk P. Lima JC, Langohr IM, Chouljenko VN, Kousoulas KG. The Oncolytic herpes simplex virus type-1 (HSV-1) vaccine strain VC2 causes intratumor infiltration of functionally active T cells and inhibition of tumor metastasis and pro-tumor genes VEGF and PDL1 expression in the 4T1/Balb/c mouse model of stage four breast cancer. Front Mol Biosci 2023; 10:1199068. [PMID: 37388243 PMCID: PMC10303929 DOI: 10.3389/fmolb.2023.1199068] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Accepted: 05/31/2023] [Indexed: 07/01/2023] Open
Abstract
Introduction: Oncolytic viruses (OVs) provide new modalities for cancer therapy either alone or in combination with synergistic immunotherapies and/or chemotherapeutics. Engineered Herpes Simplex Virus Type-1 (HSV-1) has shown strong promise for the treatment of various cancers in experimental animal models as well as in human patients, with some virus strains licensed to treat human melanoma and gliomas. In the present study we evaluated the efficacy of mutant HSV-1 (VC2) in a late stage, highly metastatic 4T1 murine syngeneic. Method: VC2 was constructed VC2 using double red recombination technology. For in-vivo efficacy we utilized a late stage 4T1 syngeneic and immunocompetent BALB/cJ mouse model breast cancer model which exhibits efficient metastasis to the lung and other organs. Results: VC2 replicated efficiently in 4T1 cells and in cell culture, achieving titers similar to those in African monkey kidney (Vero) cells. Intra-tumor treatment with VC2 did not appreciably reduce average primary tumor sizes but a significant reduction of lung metastasis was noted in mice treated intratumorally with VC2, but not with ultraviolet-inactivated VC2. This reduction of metastasis was associated with increased T cell infiltration comprised of CD4+ and CD4+CD8+ double-positive T cells. Characterization of purified tumor infiltrating T cells revealed a significant improvement in their proliferation ability compared to controls. In addition, significant T cell infiltration was observed in the metastatic nodules associated with reduction of pro-tumor PD-L1 and VEGF gene transcription. Conclusion: These results show that VC2 therapy can improve anti-tumor response associated with a better control of tumor metastasis. improve T cell responses and reduce pro-tumor biomarker gene transcription. VC2 holds promise for further development as an oncolytic and immunotherapeutic approach to treat breast and other cancers.
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Affiliation(s)
- Rafiq Nabi
- Department of Pathobiological Sciences, Louisiana State University School of Veterinary Medicine, Baton Rouge, LA, United States
- Division of Biotechnology and Molecular Medicine, School of Veterinary Medicine, Baton Rouge, LA, United States
| | - Farhana Musarrat
- Department of Pathobiological Sciences, Louisiana State University School of Veterinary Medicine, Baton Rouge, LA, United States
- Division of Biotechnology and Molecular Medicine, School of Veterinary Medicine, Baton Rouge, LA, United States
| | - Jose Cesar Menk P. Lima
- Department of Pathobiological Sciences, Louisiana State University School of Veterinary Medicine, Baton Rouge, LA, United States
| | - Ingeborg M. Langohr
- Global Discovery Pathology, Translational Models Research Platform, Sanofi, Cambridge, MA, United States
| | - Vladimir N. Chouljenko
- Department of Pathobiological Sciences, Louisiana State University School of Veterinary Medicine, Baton Rouge, LA, United States
- Division of Biotechnology and Molecular Medicine, School of Veterinary Medicine, Baton Rouge, LA, United States
| | - Konstantin G. Kousoulas
- Department of Pathobiological Sciences, Louisiana State University School of Veterinary Medicine, Baton Rouge, LA, United States
- Division of Biotechnology and Molecular Medicine, School of Veterinary Medicine, Baton Rouge, LA, United States
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9
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Mrozik A, Sellier Y, Lemaitre D, Gaucher L. Evaluation of Midwives' Practises on Herpetic Infections during Pregnancy: A French Vignette-Based Study. Healthcare (Basel) 2023; 11:healthcare11030364. [PMID: 36766939 PMCID: PMC9914294 DOI: 10.3390/healthcare11030364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 01/21/2023] [Accepted: 01/25/2023] [Indexed: 02/01/2023] Open
Abstract
(1) Background: One out of two pregnant women has a history of herpes infection. Initial infections have a high risk of neonatal transmission. Our objective was to analyse the professional practises of midwives regarding the management of herpes infections during pregnancy in France; (2) Methods: A national survey conducted via an online self-questionnaire, including clinical vignettes for which the midwives proposed a diagnosis, a drug treatment, a mode of birth, and a prognosis. These responses were used to evaluate the conformity of the responses to the guidelines, as well as the influence of certain criteria, such as mode of practise and experience; (3) Results: Of 728 responses, only 26.1% of the midwives reported being aware of the 2017 clinical practise guidelines. The midwives proposed taking the appropriate actions in 56.1% of the responses in the case of a recurrence, and in 95.1% of the responses in the case of a primary infection. For the specific, high-risk case of a nonprimary initial infection at 38 weeks of gestation, reporting knowledge of the recommendations improved the compliance of the proposed care by 40% (p = 0.02). However, 33.8% of the midwives underestimated the neonatal risk at term after a primary initial infection, and 43% underestimated the risk after a primary initial infection at term; (4) Conclusions: The majority of reported practises were compliant despite a low level of knowledge of the guidelines. The dissemination of guidelines may be important to improve information and adherence to appropriate therapeutic practise.
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Affiliation(s)
- Adrian Mrozik
- Obstetric Department, Hospital Group Paris Saint Joseph, 75014 Paris, France
- French College of Midwives (Collège National des Sages-Femmes de France, CNSF), 75010 Paris, France
| | - Yann Sellier
- French College of Midwives (Collège National des Sages-Femmes de France, CNSF), 75010 Paris, France
- EA 7328, Fetal Medicine Department Necker Hospital France, AP-HP, 92150 Suresnes, France
- School of Maieutics of Foch, UVSQ, 78180 Montigny-le-Bretonneux, France
| | - Déborah Lemaitre
- French College of Midwives (Collège National des Sages-Femmes de France, CNSF), 75010 Paris, France
| | - Laurent Gaucher
- French College of Midwives (Collège National des Sages-Femmes de France, CNSF), 75010 Paris, France
- Public Health Unit, Hospices Civils de Lyon, 69500 Bron, France
- INSERM U1290, Research on Healthcare Performance (RESHAPE), Claude Bernard Lyon 1 University, 69008 Lyon, France
- Geneva School of Health Sciences, HES-SO University of Applied Sciences and Arts Western Switzerland, 1206 Geneva, Switzerland
- Correspondence:
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10
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Clark CM, Jambunathan N, Collantes TMA, Kousoulas KG. Inactivation of the UL37 Deamidase Enhances Virus Replication and Spread of the HSV-1(VC2) Oncolytic Vaccine Strain and Secretion of GM-CSF. Viruses 2023; 15:367. [PMID: 36851581 PMCID: PMC9961126 DOI: 10.3390/v15020367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 01/18/2023] [Accepted: 01/19/2023] [Indexed: 01/31/2023] Open
Abstract
The HSV-1 (VC2) live-attenuated vaccine strain was engineered with specific deletions in the amino termini of glycoprotein K (gK) and membrane protein UL20, rendering the virus unable to enter neurons and establish latency. VC2 replicates efficiently in epithelial cell culture but produces lower viral titers and smaller viral plaques than its parental HSV-1 (F) wild-type virus. VC2 is an effective live-attenuated vaccine against HSV-1 and HSV-2 infections in mice and guinea pigs and an anti-tumor immunotherapeutic and oncolytic virus against melanoma and breast cancer in mouse models. Previously, we reported that the gK/UL20 complex interacts with the UL37 tegument protein, and this interaction is essential for virion intracellular envelopment and egress. To investigate the potential role of the UL37 deamidase functions, the recombinant virus FC819S and VC2C819S were constructed with a C819S substitution to inactivate the UL37 predicted deamidase active site on an HSV-1(F) and HSV-1(VC2) genetic background, respectively. FC819S replicated to similar levels with HSV-1(F) and produced similar size viral plaques. In contrast, VC2C819S replication was enhanced, and viral plaques increased in size, approaching those of the wild-type HSV-1(F) virus. FC819S infection of cell cultures caused enhanced GM-CSF secretion in comparison to HSV-1(F) across several cell lines, including HEp2 cells and cancer cell lines, DU145 (prostate) and Panc 04.03 (pancreas), and primary mouse peritoneal cells. VC2 infection of these cell lines caused GM-CSF secretion at similar levels to FC819S infection. However, the VC2C819S virus did not exhibit any further enhancement of GM-CSF secretion compared to the VC2 virus. These results suggest that the UL37 deamidation functions in conjunction with the gK/UL20 complex to facilitate virus replication and GM-CSF secretion.
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Affiliation(s)
- Carolyn M. Clark
- Division of Biotechnology and Molecular Medicine, Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA
| | | | - Therese M. A. Collantes
- Division of Biotechnology and Molecular Medicine, Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA
- College of Veterinary Medicine, University of the Philippines Los Baños, Los Baños 4031, Laguna, Philippines
| | - Konstantin G. Kousoulas
- Division of Biotechnology and Molecular Medicine, Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA
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11
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Li X, Hu W, Shen J, Li M, Gong W. Targeting proteasome enhances anticancer activity of oncolytic HSV-1 in colorectal cancer. Virology 2023; 578:13-21. [PMID: 36434905 DOI: 10.1016/j.virol.2022.11.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 10/24/2022] [Accepted: 11/03/2022] [Indexed: 11/13/2022]
Abstract
Herpes simplex virus 1 (HSV-1) has been widely used to treat various cancers, but its efficacy is limited. Studies indicated that combining HSV-1 and chemotherapy drugs can effectively improve the lethality of HSV-1 in tumor cells, which has a synergistic effect. Here, we explored the oncolytic effect and mechanism of bortezomib and HSV-1 on colorectal cancer cells, HCT116 and Caco-2. First, we selected four drugs to detect cell viability and found that the strongest HSV-1-promoting effect was achieved using bortezomib + HSV-1 treatment. Bortezomib combined with HSV-1 treatment significantly upregulated the expression of heat shock proteins, endoplasmic reticulum stress-related proteins and apoptosis-related proteins, while Bcl-2 was downregulated. JC-1 staining revealed that combining bortezomib and HSV-1 promotes cell apoptosis. In addition, bortezomib + oHSV-1 treatment effectively inhibit tumor growth. These results indicate that bortezomib combined with HSV-1 induce intense endoplasmic reticulum stress and activate the caspase-12 apoptosis pathway, killing tumor cells.
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Affiliation(s)
- Xiaxi Li
- Department of Gastroenterology, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong, China
| | - Wei Hu
- Department of Gastroenterology, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong, China
| | - Jiangang Shen
- Department of Gastroenterology, People's Hospital of Longhua District of Shenzhen, Shenzhen, Guangdong, China
| | - Mingsong Li
- Department of Gastroenterology, Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
| | - Wei Gong
- Department of Gastroenterology, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong, China.
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12
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Gmyrek GB, Berube AN, Sjoelund VH, Carr DJJ. HSV-1 0∆NLS vaccine elicits a robust B lymphocyte response and preserves vision without HSV-1 glycoprotein M or thymidine kinase recognition. Sci Rep 2022; 12:15920. [PMID: 36151255 PMCID: PMC9508094 DOI: 10.1038/s41598-022-20180-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Accepted: 09/08/2022] [Indexed: 11/30/2022] Open
Abstract
Effective experimental prophylactic vaccines against viral pathogens such as herpes simplex virus type 1 (HSV-1) have been shown to protect the host through T and/or B lymphocyte-driven responses. Previously, we found a live-attenuated HSV-1 mutant, 0ΔNLS used as a prophylactic vaccine, provided significant protection against subsequent ocular HSV-1 challenge aligned with a robust neutralizing antibody response. Yet, how the virus mutant elicited the humoral immune response relative to parental virus was unknown. Herein, we present the characterization of B cell subsets in vaccinated mice at times after primary vaccination and following boost compared to the parental virus, termed GFP105. We found that 0∆NLS-vaccinated mice possessed more CD4+ follicular helper T (TFH) cells, germinal B cells and class-switched B cells within the first 7 days post-vaccination. Moreover, 0∆NLS vaccination resulted in an increase in plasmablasts and plasma cells expressing amino-acid transporter CD98 along with an elevated titer of HSV-1-specific antibody compared to GFP105-vaccinated animals. Furthermore, O∆NLS-vaccine-induced CD4+ (TFH) cells produced significantly more IL-21 compared to mice immunized with the parental HSV-1 strain. In contrast, there were no differences in the number of regulatory B cells comparing the two groups of immunized mice. In comparing sera recognition of HSV-1-encoded proteins, it was noted antiserum from GFP105-vaccinated mice immunoprecipitated HSV-1 thymidine kinase (TK) and glycoprotein M (gM) whereas sera from 0∆NLS-immunized mice did not even though both groups of vaccinated mice displayed similar neutralizing antibody titers to HSV-1 and were highly resistant to ocular HSV-1 challenge. Collectively, the results suggest (1) the live-attenuated HSV-1 mutant 0∆NLS elicits a robust B cell response that drives select B cell responses greater than the parental HSV-1 and (2) HSV-1 TK and gM are likely expendable components in efficacy of a humoral response to ocular HSV-1 infection.
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Affiliation(s)
- Grzegorz B. Gmyrek
- grid.266902.90000 0001 2179 3618Departments of Ophthalmology, The University of Oklahoma Health Sciences Center (OUHSC), 608 Stanton L. Young Blvd, DMEI PA415, Oklahoma City, OK 73104 USA
| | - Amanda N. Berube
- grid.266902.90000 0001 2179 3618Departments of Ophthalmology, The University of Oklahoma Health Sciences Center (OUHSC), 608 Stanton L. Young Blvd, DMEI PA415, Oklahoma City, OK 73104 USA
| | - Virginie H. Sjoelund
- grid.266902.90000 0001 2179 3618Laboratory for Molecular Biology and Cytometry Research, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104 USA
| | - Daniel J. J. Carr
- grid.266902.90000 0001 2179 3618Departments of Ophthalmology, The University of Oklahoma Health Sciences Center (OUHSC), 608 Stanton L. Young Blvd, DMEI PA415, Oklahoma City, OK 73104 USA ,grid.266902.90000 0001 2179 3618Microbiology and Immunology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104 USA
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13
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Efficacy of an HSV-1 Neuro-Attenuated Vaccine in Mice Is Reduced by Preventing Viral DNA Replication. Viruses 2022; 14:v14050869. [PMID: 35632611 PMCID: PMC9144315 DOI: 10.3390/v14050869] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 04/18/2022] [Accepted: 04/19/2022] [Indexed: 02/05/2023] Open
Abstract
We previously isolated an HSV-1 mutant, KOS-NA, that contains two non-synonymous mutations in UL39. One of the mutations, resulting in an R950H amino acid substitution in ICP6, renders KOS-NA severely neuro-attenuated and significantly reduces HSV-1 latency. Vaccination of mice with KOS-NA prior to corneal challenge provides significant protection against HSV-1-mediated eye diseases even at a very low immunizing dose, indicating its utility as a vaccine scaffold. Because KOS-NA contains a neuro-attenuating mutation in a single gene, we sought to improve its safety by deleting a portion of the UL29 gene whose protein product, ICP8, is essential for viral DNA replication. Whereas KOS-NA reduced replication of HSV-1 challenge virus in the corneal epithelium and protected mice against blepharitis and keratitis induced by the challenge virus, KOS-NA/8- and an ICP8- virus were significantly less efficacious except at higher doses. Our results suggest that the capacity to replicate, even at significantly reduced levels compared with wild-type HSV-1, may be an important feature of an effective vaccine. Means to improve safety of attenuated viruses as vaccines without compromising efficacy should be sought.
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14
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Zhen X, Xu X, Shao X, Tian H, Xu J, Zhu B, Zuo Y, Zhang L, Yu Y. Risk factors of herpes simplex virus reactivation after surgery for primary trigeminal neuralgia. J Neurovirol 2022; 28:367-373. [PMID: 35334082 DOI: 10.1007/s13365-022-01064-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 01/20/2022] [Accepted: 02/10/2022] [Indexed: 11/30/2022]
Abstract
The objective of this study is to investigate the risk factors of oral or facial herpes simplex virus (HSV-1) infection after primary trigeminal neuralgia (PTN). The clinical data of 33 PTN patients admitted by the same surgeon in the neurosurgery were retrospectively analyzed. Among the 33 patients, 26 patients underwent microvascular decompression (MVD), 6 patients who have not been found the clear offending vessels during the operation underwent partial sensory rhizotomy (PSR), and only one underwent adhesive band separation. Thirteen patients with postoperative oral and facial HSV-1 infection were selected as the herpes group, and the remaining 20 patients without postoperative oral and facial HSV-1 infection were selected as the non-herpes group. The differences between the two groups were compared by statistical analysis of factors such as gender, age, operation mode, operation time, and serum HSV-1 antibody titer value before surgery. Compared with the non-herpes group, there were no statistically significant differences in sex ratio (P = 0.930), age composition (P = 0.261), or disease profile (P = 0.226). Twenty-six patients underwent MVD operation, eight of whom were infected, and the difference between the two groups was statistically significant (P = 0.029). The operation time of the herpes group was 10-30 min, which was significantly longer than that of the non-herpes group. The difference in operation time between the two groups was statistically significant (P = 0.023). Serum HSV-1-IgM was negative (< 0.9 COI) in all patients before surgery, but the positive rate of HSV-1-IgG (≥ 1.1 COI) was 97%, and the titer was greater than four times in 97% (32/33) of patients. The titer of IgG antibody in the herpes group was significantly lower than that in the non-herpes group, and the difference between the two groups was statistically significant (P = 0.017). The serum HSV-1-IgG in most of the PTN patients was positive. Latent HSV-1 in the trigeminal ganglion may be reactivate after PTN surgery to produce ipsilateral oral and facial herpes infection. The infection of HSV-1 reactivation after PTN surgery was positively correlated with the operation time but negatively correlated with the titer of HSV-1-IgG antibody before PTN surgery. The incidence of HSV-1 infection after PTN operation is related to different surgical procedures.
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Affiliation(s)
- Xueke Zhen
- Department of Neurosurgery, China-Japan Friendship Hospital, No. 2 East Cherry Street, Chaoyang District, Beijing, 100029, China
| | - Xiaoli Xu
- Department of Neurosurgery, China-Japan Friendship Hospital, No. 2 East Cherry Street, Chaoyang District, Beijing, 100029, China
| | - Xu Shao
- Department of Neurosurgery, China-Japan Friendship Hospital, No. 2 East Cherry Street, Chaoyang District, Beijing, 100029, China
| | - Hong Tian
- Department of Neurosurgery, China-Japan Friendship Hospital, No. 2 East Cherry Street, Chaoyang District, Beijing, 100029, China
| | - Jun Xu
- Department of Neurosurgery, China-Japan Friendship Hospital, No. 2 East Cherry Street, Chaoyang District, Beijing, 100029, China
| | - Bin Zhu
- Department of Neurosurgery, China-Japan Friendship Hospital, No. 2 East Cherry Street, Chaoyang District, Beijing, 100029, China
| | - Ying Zuo
- Department of Neurosurgery, China-Japan Friendship Hospital, No. 2 East Cherry Street, Chaoyang District, Beijing, 100029, China
| | - Li Zhang
- Department of Neurosurgery, China-Japan Friendship Hospital, No. 2 East Cherry Street, Chaoyang District, Beijing, 100029, China
| | - Yanbing Yu
- Department of Neurosurgery, China-Japan Friendship Hospital, No. 2 East Cherry Street, Chaoyang District, Beijing, 100029, China.
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15
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Rider PJF, Kamil M, Yilmaz I, Atmaca HN, Kalkan-Yazici M, Ziya Doymaz M, Kousoulas KG, Aly ASI. An Attenuated HSV-1-Derived Malaria Vaccine Expressing Liver-Stage Exported Proteins Induces Sterilizing Protection against Infectious Sporozoite Challenge. Vaccines (Basel) 2022; 10:vaccines10020300. [PMID: 35214758 PMCID: PMC8875294 DOI: 10.3390/vaccines10020300] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 02/07/2022] [Accepted: 02/10/2022] [Indexed: 02/04/2023] Open
Abstract
Here, we present the construction of an attenuated herpes simplex virus type-1 (HSV-1)-vectored vaccine, expressing three liver-stage (LS) malaria parasite exported proteins (EXP1, UIS3 and TMP21) as fusion proteins with the VP26 viral capsid protein. Intramuscular and subcutaneous immunizations of mice with a pooled vaccine, composed of the three attenuated virus strains expressing each LS antigen, induced sterile protection against the intravenous challenge of Plasmodium yoelii 17X-NL salivary gland sporozoites. Our data suggest that this malaria vaccine may be effective in preventing malaria parasite infection using practical routes of immunization in humans.
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Affiliation(s)
- Paul J. F. Rider
- Division of Biotechnology and Molecular Medicine, Louisiana State University, Baton Rouge, LA 70803, USA; (P.J.F.R.); (K.G.K.)
- Department of Pathobiological Sciences, Louisiana State University, Baton Rouge, LA 70803, USA
| | - Mohd Kamil
- Aly Lab, Beykoz Institute of Life Sciences and Biotechnology, Bezmialem Vakif University, Istanbul 34820, Turkey; (M.K.); (I.Y.); (H.N.A.)
| | - Ilknur Yilmaz
- Aly Lab, Beykoz Institute of Life Sciences and Biotechnology, Bezmialem Vakif University, Istanbul 34820, Turkey; (M.K.); (I.Y.); (H.N.A.)
| | - Habibe N. Atmaca
- Aly Lab, Beykoz Institute of Life Sciences and Biotechnology, Bezmialem Vakif University, Istanbul 34820, Turkey; (M.K.); (I.Y.); (H.N.A.)
| | - Merve Kalkan-Yazici
- Microbiology Lab, Beykoz Institute of Life Sciences and Biotechnology, Bezmialem Vakif University, Istanbul 34820, Turkey; (M.K.-Y.); (M.Z.D.)
| | - Mehmet Ziya Doymaz
- Microbiology Lab, Beykoz Institute of Life Sciences and Biotechnology, Bezmialem Vakif University, Istanbul 34820, Turkey; (M.K.-Y.); (M.Z.D.)
| | - Konstantin G. Kousoulas
- Division of Biotechnology and Molecular Medicine, Louisiana State University, Baton Rouge, LA 70803, USA; (P.J.F.R.); (K.G.K.)
- Department of Pathobiological Sciences, Louisiana State University, Baton Rouge, LA 70803, USA
| | - Ahmed S. I. Aly
- Aly Lab, Beykoz Institute of Life Sciences and Biotechnology, Bezmialem Vakif University, Istanbul 34820, Turkey; (M.K.); (I.Y.); (H.N.A.)
- Correspondence:
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16
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Uche IK, Stanfield BA, Rudd JS, Kousoulas KG, Rider PJF. Utility of a Recombinant HSV-1 Vaccine Vector for Personalized Cancer Vaccines. Front Mol Biosci 2022; 9:832393. [PMID: 35155582 PMCID: PMC8826227 DOI: 10.3389/fmolb.2022.832393] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Accepted: 01/04/2022] [Indexed: 11/17/2022] Open
Abstract
Current approaches to cancer immunotherapy include immune checkpoint inhibitors, cancer vaccines, and adoptive cellular therapy. These therapies have produced significant clinical success for specific cancers, but their efficacy has been limited. Oncolytic virotherapy (OVT) has emerged as a promising immunotherapy for a variety of cancers. Furthermore, the unique characteristics of OVs make them a good choice for delivering tumor peptides/antigens to induce enhanced tumor-specific immune responses. The first oncolytic virus (OV) approved for human use is the attenuated herpes simplex virus type 1 (HSV-1), Talimogene laherparepvec (T-VEC) which has been FDA approved for the treatment of melanoma in humans. In this study, we engineered the recombinant oncolytic HSV-1 (oHSV) VC2-OVA expressing a fragment of ovalbumin (OVA) as a fusion protein with VP26 virion capsid protein. We tested the ability of VC2-OVA to act as a vector capable of stimulating strong, specific antitumor immunity in a syngeneic murine melanoma model. Therapeutic vaccination with VC2-OVA led to a significant reduction in colonization of tumor cells in the lungs of mice intravenously challenged B16cOVA cells. In addition, VC2-OVA induced a potent prophylactic antitumor response and extended survival of mice that were intradermally engrafted with B16cOVA tumors compared with mice immunized with control virus.
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Affiliation(s)
- Ifeanyi Kingsley Uche
- Division of Biotechnology and Molecular Medicine Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA, United States
- Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA, Untied States
| | - Brent A. Stanfield
- Division of Biotechnology and Molecular Medicine Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA, United States
- Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA, Untied States
| | - Jared S. Rudd
- Division of Biotechnology and Molecular Medicine Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA, United States
- Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA, Untied States
| | - Konstantin G. Kousoulas
- Division of Biotechnology and Molecular Medicine Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA, United States
- Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA, Untied States
- *Correspondence: Konstantin G. Kousoulas, ; Paul J. F. Rider,
| | - Paul J. F. Rider
- Division of Biotechnology and Molecular Medicine Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA, United States
- Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA, Untied States
- *Correspondence: Konstantin G. Kousoulas, ; Paul J. F. Rider,
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17
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Nabi R, Lewin AC, Collantes TM, Chouljenko VN, Kousoulas KG. Intramuscular Vaccination With the HSV-1(VC2) Live-Attenuated Vaccine Strain Confers Protection Against Viral Ocular Immunopathogenesis Associated With γδT Cell Intracorneal Infiltration. Front Immunol 2021; 12:789454. [PMID: 34868077 PMCID: PMC8634438 DOI: 10.3389/fimmu.2021.789454] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Accepted: 10/25/2021] [Indexed: 11/18/2022] Open
Abstract
Herpes simplex virus type-1 (HSV-1) ocular infection is one of the leading causes of infectious blindness in developed countries. The resultant herpetic keratitis (HK) is caused by an exacerbated reaction of the adaptive immune response that persists beyond virus clearance causing substantial damage to the cornea. Intramuscular immunization of mice with the HSV-1(VC2) live-attenuated vaccine strain has been shown to protect mice against lethal ocular challenge. Herein, we show that following ocular challenge, VC2 vaccinated animals control ocular immunopathogenesis in the absence of neutralizing antibodies on ocular surfaces. Ocular protection is associated with enhanced intracorneal infiltration of γδ T cells compared to mock-vaccinated animals. The observed γδ T cellular infiltration was inversely proportional to the infiltration of neutrophils, the latter associated with exacerbated tissue damage. Inhibition of T cell migration into ocular tissues by the S1P receptors agonist FTY720 produced significant ocular disease in vaccinated mice and marked increase in neutrophil infiltration. These results indicate that ocular challenge of mice immunized with the VC2 vaccine induce a unique ocular mucosal response that leads into the infiltration of γδ T cells resulting in the amelioration of infection-associated immunopathogenesis.
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MESH Headings
- Animals
- Chemotaxis, Leukocyte
- Cornea/immunology
- Cornea/pathology
- Cornea/virology
- Cytokines/metabolism
- Disease Models, Animal
- Female
- Herpes Simplex Virus Vaccines/administration & dosage
- Herpes Simplex Virus Vaccines/immunology
- Herpesvirus 1, Human/immunology
- Herpesvirus 1, Human/pathogenicity
- Host-Pathogen Interactions
- Injections, Intramuscular
- Intraepithelial Lymphocytes/immunology
- Intraepithelial Lymphocytes/virology
- Keratitis, Herpetic/immunology
- Keratitis, Herpetic/pathology
- Keratitis, Herpetic/prevention & control
- Keratitis, Herpetic/virology
- Lymphangiogenesis
- Mice, Inbred BALB C
- Neovascularization, Pathologic
- Neutrophil Infiltration
- Vaccination
- Vaccines, Attenuated/administration & dosage
- Vaccines, Attenuated/immunology
- Mice
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Affiliation(s)
- Rafiq Nabi
- Department of Pathobiological Science, Louisiana State University School of Veterinary Medicine, Baton Rouge, LA, United States
| | - Andrew C. Lewin
- Department of Veterinary Clinical Sciences, Louisiana State University School of Veterinary Medicine, Baton Rouge, LA, United States
| | - Therese M. Collantes
- Department of Pathobiological Science, Louisiana State University School of Veterinary Medicine, Baton Rouge, LA, United States
| | - Vladimir N. Chouljenko
- Department of Pathobiological Science, Louisiana State University School of Veterinary Medicine, Baton Rouge, LA, United States
| | - Konstantin G. Kousoulas
- Department of Pathobiological Science, Louisiana State University School of Veterinary Medicine, Baton Rouge, LA, United States
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18
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Carr DJJ, Berube A, Gershburg E. The Durability of Vaccine Efficacy against Ocular HSV-1 Infection Using ICP0 Mutants 0∆NLS and 0∆RING Is Lost over Time. Pathogens 2021; 10:1470. [PMID: 34832625 PMCID: PMC8618588 DOI: 10.3390/pathogens10111470] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 11/05/2021] [Accepted: 11/10/2021] [Indexed: 12/20/2022] Open
Abstract
Vaccines to viral pathogens in experimental animal models are often deemed successful if immunization enhances resistance of the host to virus challenge as measured by cumulative survival, reduction in virus replication and spread and/or lessen or eliminate overt tissue pathology. Furthermore, the duration of the protective response against challenge is another important consideration that drives a vaccination regimen. In the current study, we assessed the durability of two related vaccines, 0∆NLS and 0∆RING, against ocular herpes simplex virus type 1 (HSV-1) challenge in mice thirty days (short-term) and one year (long-term) following the vaccine boost. The short-term vaccine efficacy study found the 0∆RING vaccine to be nearly equivalent to the 0∆NLS vaccine in comparison to vehicle-vaccinated mice in terms of controlling virus replication and preserving the visual axis. By comparison, the long-term assessment of the two vaccines found notable differences and less efficacy overall as noted below. Specifically, the results show that in comparison to vehicle-vaccinated mice, the 0∆NLS and 0∆RING vaccinated groups were more resistant in terms of survival and virus shedding following ocular challenge. Moreover, 0∆NLS vaccinated mice also possessed significantly less infectious virus in the peripheral and central nervous systems but not the cornea compared to mice vaccinated with vehicle or 0∆RING which had similar levels. However, all vaccinated groups showed similar levels of blood and lymphatic vessel genesis into the central cornea 30 days post infection. Likewise, corneal opacity was also similar among all groups of vaccinated mice following infection. Functionally, the blink response and visual acuity were 25-50% lower in vaccinated mice 30 days post infection compared to measurements taken prior to infection. The results demonstrate a dichotomy between resistance to infection and functional performance of the visual axis that collectively show an overall loss in vaccine efficacy long-term in comparison to short-term studies in a conventional prime-boost protocol.
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Affiliation(s)
- Daniel J. J. Carr
- Department of Ophthalmology, Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Amanda Berube
- Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA;
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Lin TL, Cheng C, Zeng WT, Duan F, Pei YH, Liu XP, Shang F, Wu KL. Anti-viral activity of Staphylococcus aureus lysates against herpes simplex virus type-I infection: an in vitro and in vivo study. Int J Ophthalmol 2021; 14:1463-1472. [PMID: 34667721 DOI: 10.18240/ijo.2021.10.01] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Accepted: 02/05/2021] [Indexed: 02/08/2023] Open
Abstract
AIM To investigate the effect of Staphylococcus aureus (S. aures) lysates (SALs) on herpes simplex virus type-I (HSV1) infection in human corneal epithelial (HCE) cells and in a mouse model of HSV1 keratitis. METHODS HCE, Vero, HeLa, and BV2 cells were infected with HSV1 [HSV1 f strain, HSV1f; HSV-1-H129 with green fluorescent protein (GFP) knock-in, HSV1g]. Pre- or post-infection, SAL at various concentrations was added to the culture medium for 24h. GFP fluorescence in HSV1g or plaque formation by HSV1f were examined. The effects of heat-treated SAL, precooled acetone-precipitated SAL, and SAL subjected to ultrafiltration (100 kDa) were evaluated. The effects of other bacterial components and lysates on HSV1 infection were also tested, including lipoteichoic acid (LTA), peptidoglycan (PGN), staphylococcal protein A (SPA), and α-hemolysin from S. aureus (α-toxin) as well as lysates from a wild-type S. aureus strain, S. epidermidis, and Escherichia coli (W-SAL, SEL, and ECL, respectively). In addition, SAL eye drops were applied topically to BALB/c mice with HSV1 keratitis, followed by in vivo observations. RESULTS The cytopathic effect, plaque formation (HSV1f), and GFP expression (HSV1g) in infected cells were inhibited by SAL in a dose-dependent manner. The active component of SAL (≥100 kDa) was heat-sensitive and retained activity after acetone precipitation. In HSV1g-infected cells, treatment with LTA-sa, α-toxin, PGN-sa, or SPA did not inhibit GFP expression. SAL, W-SAL, and SEL (but not ECL) decreased GFP expression. In mice with HSV1 keratitis, SAL reduced corneal lesions by 71%. CONCLUSION The results of this study demonstrate that SAL can be used to inhibit HSV1 infection, particularly keratitis. Further studies are needed to determine the active components and mechanism underlying the effects of SAL.
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Affiliation(s)
- Tian-Lan Lin
- Zhongshan Ophthalmic Center, State Key Laboratory of Ophthalmology, Sun Yat-sen University, Guangzhou 510060, Guangdong Province, China
| | - Chao Cheng
- Zhongshan Ophthalmic Center, State Key Laboratory of Ophthalmology, Sun Yat-sen University, Guangzhou 510060, Guangdong Province, China
| | - Wei-Ting Zeng
- Zhongshan Ophthalmic Center, State Key Laboratory of Ophthalmology, Sun Yat-sen University, Guangzhou 510060, Guangdong Province, China
| | - Fang Duan
- Zhongshan Ophthalmic Center, State Key Laboratory of Ophthalmology, Sun Yat-sen University, Guangzhou 510060, Guangdong Province, China
| | - Yin-Hui Pei
- Zhongshan Ophthalmic Center, State Key Laboratory of Ophthalmology, Sun Yat-sen University, Guangzhou 510060, Guangdong Province, China
| | - Xiu-Ping Liu
- Zhongshan Ophthalmic Center, State Key Laboratory of Ophthalmology, Sun Yat-sen University, Guangzhou 510060, Guangdong Province, China
| | - Fu Shang
- Zhongshan Ophthalmic Center, State Key Laboratory of Ophthalmology, Sun Yat-sen University, Guangzhou 510060, Guangdong Province, China
| | - Kai-Li Wu
- Zhongshan Ophthalmic Center, State Key Laboratory of Ophthalmology, Sun Yat-sen University, Guangzhou 510060, Guangdong Province, China
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Two Sides to Every Story: Herpes Simplex Type-1 Viral Glycoproteins gB, gD, gH/gL, gK, and Cellular Receptors Function as Key Players in Membrane Fusion. Viruses 2021; 13:v13091849. [PMID: 34578430 PMCID: PMC8472851 DOI: 10.3390/v13091849] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 09/02/2021] [Accepted: 09/04/2021] [Indexed: 12/21/2022] Open
Abstract
Herpes simplex virus type-1 (HSV-1) and type-2 (HSV-2) are prototypical alphaherpesviruses that are characterized by their unique properties to infect trigeminal and dorsal root ganglionic neurons, respectively, and establish life-long latent infections. These viruses initially infect mucosal epithelial tissues and subsequently spread to neurons. They are associated with a significant disease spectrum, including orofacial and ocular infections for HSV-1 and genital and neonatal infections for HSV-2. Viral glycoproteins within the virion envelope bind to specific cellular receptors to mediate virus entry into cells. This is achieved by the fusion of the viral envelope with the plasma membrane. Similarly, viral glycoproteins expressed on cell surfaces mediate cell-to-cell fusion and facilitate virus spread. An interactive complex of viral glycoproteins gB, gD/gH/gL, and gK and other proteins mediate these membrane fusion phenomena with glycoprotein B (gB), the principal membrane fusogen. The requirement for the virion to enter neuronal axons suggests that the heterodimeric protein complex of gK and membrane protein UL20, found only in alphaherpesviruses, constitute a critical determinant for neuronal entry. This hypothesis was substantiated by the observation that a small deletion in the amino terminus of gK prevents entry into neuronal axons while allowing entry into other cells via endocytosis. Cellular receptors and receptor-mediated signaling synergize with the viral membrane fusion machinery to facilitate virus entry and intercellular spread. Unraveling the underlying interactions among viral glycoproteins, envelope proteins, and cellular receptors will provide new innovative approaches for antiviral therapy against herpesviruses and other neurotropic viruses.
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Stanfield BA, Kousoulas KG, Fernandez A, Gershburg E. Rational Design of Live-Attenuated Vaccines against Herpes Simplex Viruses. Viruses 2021; 13:1637. [PMID: 34452501 PMCID: PMC8402837 DOI: 10.3390/v13081637] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2021] [Revised: 08/09/2021] [Accepted: 08/13/2021] [Indexed: 12/19/2022] Open
Abstract
Diseases caused by human herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) affect millions of people worldwide and range from fatal encephalitis in neonates and herpes keratitis to orofacial and genital herpes, among other manifestations. The viruses can be shed efficiently by asymptomatic carriers, causing increased rates of infection. Viral transmission occurs through direct contact of mucosal surfaces followed by initial replication of the incoming virus in skin tissues. Subsequently, the viruses infect sensory neurons in the trigeminal and lumbosacral dorsal root ganglia, where they are primarily maintained in a transcriptionally repressed state termed "latency", which persists for the lifetime of the host. HSV DNA has also been detected in other sympathetic ganglia. Periodically, latent viruses can reactivate, causing ulcerative and often painful lesions primarily at the site of primary infection and proximal sites. In the United States, recurrent genital herpes alone accounts for more than a billion dollars in direct medical costs per year, while there are much higher costs associated with the socio-economic aspects of diseased patients, such as loss of productivity due to mental anguish. Currently, there are no effective FDA-approved vaccines for either prophylactic or therapeutic treatment of human herpes simplex infections, while several recent clinical trials have failed to achieve their endpoint goals. Historically, live-attenuated vaccines have successfully combated viral diseases, including polio, influenza, measles, and smallpox. Vaccines aimed to protect against the devastation of smallpox led to the most significant achievement in medical history: the eradication of human disease by vaccination. Recently, novel approaches toward developing safe and effective live-attenuated vaccines have demonstrated high efficacy in various preclinical models of herpetic disease. This next generation of live-attenuated vaccines has been tailored to minimize vaccine-associated side effects and promote effective and long-lasting immune responses. The ultimate goal is to prevent or reduce primary infections (prophylactic vaccines) or reduce the frequency and severity of disease associated with reactivation events (therapeutic vaccines). These vaccines' "rational" design is based on our current understanding of the immunopathogenesis of herpesviral infections that guide the development of vaccines that generate robust and protective immune responses. This review covers recent advances in the development of herpes simplex vaccines and the current state of ongoing clinical trials in pursuit of an effective vaccine against herpes simplex virus infections and associated diseases.
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Affiliation(s)
- Brent A. Stanfield
- Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA;
| | - Konstantin G. Kousoulas
- Division of Biotechnology and Molecular Medicine, Louisiana State University, Baton Rouge, LA 70803, USA
- Rational Vaccines Inc., Woburn, MA 01801, USA;
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Wijesinghe VN, Farouk IA, Zabidi NZ, Puniyamurti A, Choo WS, Lal SK. Current vaccine approaches and emerging strategies against herpes simplex virus (HSV). Expert Rev Vaccines 2021; 20:1077-1096. [PMID: 34296960 DOI: 10.1080/14760584.2021.1960162] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Introduction: Vaccine development for the disease caused by the herpes simplex virus (HSV) has been challenging over the years and is always in dire need of novel approaches for prevention and cure. To date, the HSV disease remains incurable and challenging to prevent. The disease is extremely widespread due to its high infection rate, resulting in millions of infection cases worldwide.Areas covered: This review first explains the diverse forms of HSV-related disease presentations and reports past vaccine history for the disease. Next, this review examines current and novel HSV vaccine approaches being studied and tested for efficacy and safety as well as vaccines in clinical trial phases I to III. Modern approaches to vaccine design using bioinformatics are described. Finally, we discuss measures to enhance new vaccine development pipelines for HSV.Expert opinion: Modernized approaches using in silico analysis and bioinformatics are emerging methods that exhibit potential for producing vaccines with enhanced targets and formulations. Although not yet fully established for HSV disease, we describe current studies using these approaches for HSV vaccine design to shed light on these methods. In addition, we provide up-to-date requirements of immunogenicity, adjuvant selection, and routes of administration.
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Affiliation(s)
| | - Isra Ahmad Farouk
- School of Science, Monash University, Bandar Sunway, Selangor, Malaysia
| | | | | | - Wee Sim Choo
- School of Science, Monash University, Bandar Sunway, Selangor, Malaysia
| | - Sunil Kumar Lal
- School of Science, Monash University, Bandar Sunway, Selangor, Malaysia.,Tropical Medicine & Biology Platform, Monash University, Bandar Sunway, Selangor, Malaysia
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Carr DJJ, Berube AN, Filiberti A, Gmyrek GB. Lack of neonatal Fc receptor does not diminish the efficacy of the HSV-1 0ΔNLS vaccine against ocular HSV-1 challenge. Vaccine 2021; 39:2526-2536. [PMID: 33814229 DOI: 10.1016/j.vaccine.2021.03.075] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 03/08/2021] [Accepted: 03/20/2021] [Indexed: 02/07/2023]
Abstract
The neonatal Fc receptor (FcRn) is constitutively expressed in the cornea and is up-regulated in response to herpes simplex virus type 1 (HSV-1). Previously, we found targeting cornea FcRn expression by small interfering RNA-mediated knockdown reduced the local efficacy of HSV-1 0ΔNLS vaccinated C57BL/6 mice against ocular challenge with HSV-1. The current study was undertaken to evaluate the HSV-1 0ΔNLS vaccine efficacy in FcRn deficient (FcRn KO) mice challenged with HSV-1. Whereas there was little neutralizing antibody detected in the serum of HSV-1 0ΔNLS vaccinated FcRn KO mice, these mice exhibited the same degree of protection against ocular challenge with HSV-1 as wild type (WT) C57BL/6 mice as measured by cumulative survival, infectious virus shed or retained in tissue, and corneal pathology including opacity and neovascularization. Mock-vaccinated FcRn KO mice were found to be more sensitive to ocular HSV-1 infection compared to mock-vaccinated (WT) mice in terms of cumulative survival and virus shedding. In addition, the FcRn KO mice generated significantly fewer effector (CD3+CD44+CD62L-) and central (CD3+CD44+CD62L+) memory CD8+ T cells compared to the WT mice 7 days post infection. Collectively, mock-vaccinated FcRn KO mice are susceptible to ocular HSV-1 infection but HSV-1 0ΔNLS vaccinated FcRn KO mice are resistant suggesting that in addition to the FcRn, other pathways are involved in mediating the protective effect of the HSV-1 0ΔNLS vaccine against subsequent HSV-1 challenge.
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Affiliation(s)
- Daniel J J Carr
- Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
| | - Amanda N Berube
- Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Adrian Filiberti
- Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Grzegorz B Gmyrek
- Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
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Novel Oncolytic Herpes Simplex Virus 1 VC2 Promotes Long-Lasting, Systemic Anti-melanoma Tumor Immune Responses and Increased Survival in an Immunocompetent B16F10-Derived Mouse Melanoma Model. J Virol 2021; 95:JVI.01359-20. [PMID: 33177208 PMCID: PMC7925097 DOI: 10.1128/jvi.01359-20] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Accepted: 10/28/2020] [Indexed: 12/31/2022] Open
Abstract
Current oncolytic virotherapies possess limited response rates. However, when certain patient selection criteria are used, oncolytic virotherapy response rates have been shown to increase. Oncolytic virotherapy (OVT) is now understood to be an immunotherapy that uses viral infection to liberate tumor antigens in an immunogenic context to promote the development of antitumor immune responses. The only currently FDA-approved oncolytic virotherapy, T-Vec, is a modified type 1 herpes simplex virus (HSV-1). While T-Vec is associated with limited response rates, its modest efficacy supports the continued development of novel OVT viruses. Herein, we test the efficacy of a recombinant HSV-1, VC2, as an OVT in a syngeneic B16F10-derived mouse model of melanoma. VC2 possesses mutations that block its ability to enter neurons via axonal termini. This greatly enhances its safety profile by precluding the ability of the virus to establish latent infection. VC2 has been shown to be a safe, effective vaccine against both HSV-1 and HSV-2 infection in mice, guinea pigs, and nonhuman primates. We found that VC2 slows tumor growth rates and that VC2 treatment significantly enhances survival of tumor-engrafted, VC2-treated mice over control treatments. VC2-treated mice that survived initial tumor engraftment were resistant to a second engraftment as well as colonization of lungs by intravenous introduction of tumor cells. We found that VC2 treatment induced substantial increases in intratumoral T cells and a decrease in immunosuppressive regulatory T cells. This immunity was critically dependent on CD8+ T cells and less dependent on CD4+ T cells. Our data provide significant support for the continued development of VC2 as an OVT for the treatment of human and animal cancers. IMPORTANCE Current oncolytic virotherapies possess limited response rates. However, when certain patient selection criteria are used, oncolytic virotherapy response rates have been shown to increase. This, in addition to the increased response rates of oncolytic virotherapy in combination with other immunotherapies, suggests that oncolytic viruses possess significant therapeutic potential for the treatment of cancer. As such, it is important to continue to develop novel oncolytic viruses as well as support basic research into their mechanisms of efficacy. Our data demonstrate significant clinical potential for VC2, a novel type 1 oncolytic herpes simplex virus. Additionally, due to the high rates of survival and the dependence on CD8+ T cells for efficacy, our model will enable study of the immunological correlates of protection for VC2 oncolytic virotherapy and oncolytic virotherapy in general. Understanding the mechanisms of efficacious oncolytic virotherapy will inform the rational design of improved oncolytic virotherapies.
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Gmyrek GB, Filiberti A, Montgomery M, Chitrakar A, Royer DJ, Carr DJJ. Herpes Simplex Virus 1 (HSV-1) 0ΔNLS Live-Attenuated Vaccine Protects against Ocular HSV-1 Infection in the Absence of Neutralizing Antibody in HSV-1 gB T Cell Receptor-Specific Transgenic Mice. J Virol 2020; 94:e01000-20. [PMID: 32999018 PMCID: PMC7925190 DOI: 10.1128/jvi.01000-20] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Accepted: 09/21/2020] [Indexed: 12/11/2022] Open
Abstract
The contribution of T cell and antibody responses following vaccination in resistance to herpes simplex virus 1 (HSV-1) infection continues to be rigorously investigated. In the present article, we explore the contribution of CD8+ T cells specific for the major antigenic epitope for HSV-1 glycoprotein B (gB498-505, gB) in C57BL/6 mice using a transgenic mouse (gBT-I.1) model vaccinated with HSV-1 0ΔNLS. gBT-I.1-vaccinated mice did not generate a robust neutralization antibody titer in comparison to the HSV-1 0ΔNLS-vaccinated wild-type C57BL/6 counterpart. Nevertheless, the vaccinated gBT-I.1 mice were resistant to ocular challenge with HSV-1 compared to vehicle-vaccinated animals based on survival and reduced corneal neovascularization but displayed similar levels of corneal opacity. Whereas there was no difference in the virus titer recovered from the cornea comparing vaccinated mice, HSV-1 0ΔNLS-vaccinated animals possessed significantly less infectious virus during acute infection in the trigeminal ganglia (TG) and brain stem compared to the control-vaccinated group. These results correlated with a significant increase in gB-elicited interferon-γ (IFN-γ), granzyme B, and CD107a and a reduction in lymphocyte activation gene 3 (LAG-3), programmed cell death 1 (PD-1), and T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) expressed by TG infiltrating gB-specific CD8+ T cells from the HSV-1 0ΔNLS-vaccinated group. Antibody depletion of CD8+ T cells in HSV-1 0ΔNLS-vaccinated mice rendered animals highly susceptible to virus-mediated mortality similar to control-vaccinated mice. Collectively, the HSV-1 0ΔNLS vaccine is effective against ocular HSV-1 challenge, reducing ocular neovascularization and suppressing peripheral nerve virus replication in the near absence of neutralizing antibody in this unique mouse model.IMPORTANCE The role of CD8+ T cells in antiviral efficacy using a live-attenuated virus as the vaccine is complicated by the humoral immune response. In the case of the herpes simplex virus 1 (HSV-1) 0ΔNLS vaccine, the correlate of protection has been defined to be primarily antibody driven. The current study shows that in the near absence of anti-HSV-1 antibody, vaccinated mice are protected from subsequent challenge with wild-type HSV-1 as measured by survival. The efficacy is lost following depletion of CD8+ T cells. Whereas increased survival and reduction in virus replication were observed in vaccinated mice challenged with HSV-1, cornea pathology was mixed with a reduction in neovascularization but no change in opacity. Collectively, the study suggests CD8+ T cells significantly contribute to the host adaptive immune response to HSV-1 challenge following vaccination with an attenuated virus, but multiple factors are involved in cornea pathology in response to ocular virus challenge.
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Affiliation(s)
- Grzegorz B Gmyrek
- Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
| | - Adrian Filiberti
- Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
| | - Micaela Montgomery
- Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
| | - Alisha Chitrakar
- Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
| | - Derek J Royer
- Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
| | - Daniel J J Carr
- Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
- Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
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