The Amino Terminus of Herpes Simplex Virus 1 Glycoprotein K (gK) Is Required for gB Binding to Akt, Release of Intracellular Calcium, and Fusion of the Viral Envelope with Plasma Membranes

Musarrat, Farhana; Jambunathan, Nithya; Rider, Paul J. F.; Chouljenko, Vladimir N.; Kousoulas, Konstantin G.

doi:10.1128/jvi.01842-17

Cited by 32 publications

(41 citation statements)

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“…Previously, we showed that gK is involved in facilitating fusion of the viral envelope with cellular membranes during virus entry [24][25][26][27][28]. Importantly, we showed that gK (31-68aa) deletion prevented the virus from entering axonal termini of neurons in culture and prevented retrograde virion transport after ocular infection [29]. UL20 physically interacts with gK and these interactions are necessary for intracellular transport and functions of both g K and UL20 [30].…”

Section: Introductionmentioning

confidence: 80%

“…In contrast, VC2 exhibited superior protection and morbidity control against HSV-1(McKrae) lethal challenge. gk 31-68 deleted virus has been shown to defective in entering mouse neurons [42] by fusion of the viral envelope with cellular membranes [29], while it can enter into Vero cells via endocytosis and replicate in similar titers to the parental virus. This substantial difference in virus entry may induce significant downstream signaling responses that result in the observed differential efficacy in vaccine-induced protection.…”

Section: Discussionmentioning

confidence: 99%

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Intramuscular vaccination of mice with the human herpes simplex virus type-1(HSV-1) VC2 vaccine, but not its parental strain HSV-1(F) confers full protection against lethal ocular HSV-1 (McKrae) pathogenesis

et al. 2020

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Herpes simplex virus type-1 (HSV-1) can cause severe ocular infection and blindness. We have previously shown that the HSV-1 VC2 vaccine strain is protective in mice and guinea pigs against genital herpes infection following vaginal challenge with HSV-1 or HSV-2. In this study, we evaluated the efficacy of VC2 intramuscular vaccination in mice against herpetic keratitis following ocular challenge with lethal human clinical strain HSV-1(McKrae). VC2 vaccination in mice produced superior protection and morbidity control in comparison to its parental strain HSV-1(F). Specifically, after HSV-1(McKrae) ocular challenge, all VC2 vaccinated-mice survived, while 30% of the HSV-1(F)-vaccinated and 100% of the mock-vaccinated mice died post challenge. VC2-vaccinated mice did not exhibit any symptoms of ocular infection and completely recovered from initial conjunctivitis. In contrast, HSV-1(F)-vaccinated mice developed time-dependent progressive keratitis characterized by corneal opacification, while mockvaccinated animals exhibited more severe stromal keratitis characterized by immune cell infiltration and neovascularization in corneal stroma with corneal opacification. Cornea in VC2immunized mice exhibited significantly increased infiltration of CD3 + T lymphocytes and decreased infiltration of Iba1+ macrophages in comparison to mock-or HSV-1(F)-vaccinated groups. VC2 immunization produced higher virus neutralization titers than HSV-1(F) post challenge. Furthermore, VC-vaccination significantly increased the CD4 T central memory (TCM) subsets and CD8 T effector memory (TEM) subsets in the draining lymph nodes following ocular HSV-1 (McKrae) challenge, then mock-or HSV-1(F)-vaccination. These results indicate that VC2 vaccination produces a protective immune response at the site of challenge to protect against HSV-1-induced ocular pathogenesis.

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Section: Introductionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Intramuscular vaccination of mice with the human herpes simplex virus type-1(HSV-1) VC2 vaccine, but not its parental strain HSV-1(F) confers full protection against lethal ocular HSV-1 (McKrae) pathogenesis

et al. 2020

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“…Glycoprotein K (gK) is one of the 12 known glycoproteins encoded by the virus, and HSV-1 is covered by glycoproteins. gK is mainly involved in viral entry into corneal epithelial cells, membrane fusion, the intracellular spread of virions, and virion egress (86). Many studies support the viewpoint that gK plays important roles in viral replication and corneal scarring (6,87).…”

Section: The Role Of Glycoproteins In Hskmentioning

confidence: 98%

Pathogenesis of Herpes Stromal Keratitis: Immune Inflammatory Response Mediated by Inflammatory Regulators

Wang

et al. 2020

Front. Immunol.

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Herpes stromal keratitis (HSK) is one of the primary diseases that cause vision loss or even blindness after herpes simplex virus (HSV)-1 infection. HSK-associated vision impairment is predominantly due to corneal scarring and neovascularization caused by inflammation. In the infected cornea, HSV can activate innate and adaptive immune responses of host cells, which triggers a cascade of reactions that leads to the release of inflammatory cytokines, chemokines, microRNA, and other regulatory factors that have stimulating or inhibitory effects on tissue. Physiologically, host cells show homeostasis. In this review, we summarize the factors involved in HSK pathogenesis from the perspective of immunity, molecules, and pathological angiogenesis. We also describe in detail the pathogenesis of chronic inflammatory lesions of the corneal stroma in response to HSV-1 infection.

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“…Previous studies have hinted at the ability of some of these proteins to influence entry pathways. For example, gK is thought to promote entry into neurons by fusion with the plasma membrane because deletion of the N terminus of gK switches entry to endocytosis (82). gC promotes efficient endocytic entry into CHO-HVEM and primary human keratinocytes (69).…”

Section: Discussionmentioning

confidence: 99%

Contributions of the four essential entry glycoproteins to HSV-1 tropism and the selection of entry routes

Hilterbrand

Daly

Heldwein

2020

Preprint

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15Herpes Simplex viruses (HSV-1 and HSV-2) encode up to 15 glycosylated and unglycosylated 16 envelope proteins. Four of these, gB, gH, gL, and gD, are essential for entry and mediate cell-cell 17 fusion when co-expressed in uninfected, receptor-bearing cells. However, their contributions to 18 HSV-1 tropism and the selection of entry routes are unclear. To begin addressing this, we 19 previously pseudotyped VSV lacking its native glycoprotein, G, with HSV-1 glycoproteins gB, 20 gH, gL, and gD. This novel VSVDG-BHLD pseudotype recapitulated several aspects of HSV-1 21 entry: it could enter murine C10 cells, required gB, gH, gL, gD, and a cellular receptor for entry, 22 AUTHOR SUMMARY 37Different viruses enter cells by diverse routes, but how that choice is made is not always clear. 38Understanding the mechanisms behind these choices is vital for finding strategies to prevent viral 39 infections. In enveloped viruses, viral proteins embedded in the envelope accomplish this task. 40While most enveloped viruses encode one or two envelope proteins, Herpes Simplex viruses 41 (HSV) encode up to 15. Four of these are deemed essential for entry (gB, gH, gL, and gD) 42 whereas the rest have been termed non-essential. While these four proteins are essential, their 43 contributions to HSV-1 cellular tropism and entry pathways have not been fully elucidated. Here, 44we generated virions that have only the four essential HSV-1 glycoproteins on their surface. We 45show that the VSVDG-BHLD pseudotype has a narrower tropism than HSV-1 and uses different 46 entry pathways. Thus, the four essential HSV-1 entry glycoproteins alone do not define HSV-1 47 55All viruses must enter cells to initiate infection, and different viruses accomplish this task by 56 different mechanisms: some penetrate cells at the plasma membrane while others hijack host 57 endocytic pathways. Enveloped viruses -those in which the nucleocapsid is surrounded by a 58 cell-derived lipid bilayer -penetrate the cells by merging their lipid envelopes with a cellular 59 membrane, either the plasma membrane or the membrane of an endocytic vesicle following 60 endocytosis ( Fig 1) [reviewed in (1, 2)]. Viruses typically have preferred entry routes, the choice 61 of which is not always clear, and some enter different target cells by different routes. 62Understanding what routes viruses use to enter cells and how they select them may help inform 63 strategies to prevent viral infections. 64Herpes Simplex viruses (HSV-1 and HSV-2) are enveloped alphaherpesviruses that infect 65 much of the world's population for life, causing a panoply of diseases ranging from painful to 66 life-threatening (3, 4). An enduring mystery of HSV entry is how and why the virus enters 67 different cells by different routes: direct fusion with the plasma membrane [e.g., neurons, Vero 68 cells, Hep2 cells, reviewed in (5)] or by endocytosis and subsequent fusion with the endosomal 69 membrane [e.g., keratinocytes, corneal epithelial cells (6, 7)]. 70HSV-1 encodes 15 viral envelope proteins, ...

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The Amino Terminus of Herpes Simplex Virus 1 Glycoprotein K (gK) Is Required for gB Binding to Akt, Release of Intracellular Calcium, and Fusion of the Viral Envelope with Plasma Membranes

Cited by 32 publications

References 96 publications

Intramuscular vaccination of mice with the human herpes simplex virus type-1(HSV-1) VC2 vaccine, but not its parental strain HSV-1(F) confers full protection against lethal ocular HSV-1 (McKrae) pathogenesis

Intramuscular vaccination of mice with the human herpes simplex virus type-1(HSV-1) VC2 vaccine, but not its parental strain HSV-1(F) confers full protection against lethal ocular HSV-1 (McKrae) pathogenesis

Pathogenesis of Herpes Stromal Keratitis: Immune Inflammatory Response Mediated by Inflammatory Regulators

Contributions of the four essential entry glycoproteins to HSV-1 tropism and the selection of entry routes

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