scholarly journals In Vitro and In Vivo Activity, Tolerability, and Mechanism of Action of BX795 as an Antiviral against Herpes Simplex Virus 2 Genital Infection

2020 ◽  
Vol 64 (9) ◽  
Author(s):  
James Hopkins ◽  
Tejabhiram Yadavalli ◽  
Rahul Suryawanshi ◽  
Farreh Qatanani ◽  
Ipsita Volety ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Epithelial Cells ◽  
Mechanism Of Action ◽  
Nucleoside Analogs ◽  
Protein Translation ◽  
Vaginal Epithelial Cells ◽  
Simplex Virus

ABSTRACT Herpes simplex virus type 2 (HSV-2) causes recurrent lesions in the anogenital area that may be transmitted through sexual encounters. Nucleoside analogs, such as acyclovir (ACV), are currently prescribed clinically to curb this infection. However, in some cases, reduced efficacy has been observed due to the emergence of resistance against these drugs. In our previous study, we reported the discovery of a novel anti-HSV-1 small molecule, BX795, which was originally used as an inhibitor of TANK-binding kinase 1 (TBK1). In this study, we report the antiviral efficacy of BX795 on HSV-2 infection in vaginal epithelial cells in vitro at 10 μM and in vivo at 50 μM. Additionally, through biochemical assays in vitro and histopathology in vivo, we show the tolerability of BX795 in vaginal epithelial cells at concentrations as high as 80 μM. Our investigations also revealed that the mechanism of action of BX795 antiviral activity stems from the reduction of viral protein translation via inhibition of protein kinase B phosphorylation. Finally, using a murine model of vaginal infection, we show that topical therapy using 50 μM BX795 is well tolerated and efficacious in controlling HSV-2 replication.

scholarly journals Roles of TRIM32 in Corneal Epithelial Cells After Infection with Herpes Simplex Virus

2017 ◽  
Vol 43 (2) ◽  
pp. 801-811 ◽  
Author(s):  
Hao Cui ◽  
Ying Liu ◽  
Yifei Huang
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Epithelial Cells ◽  
Microbial Pathogens ◽  
Corneal Epithelial Cells ◽  
Corneal Epithelial ◽  
Simplex Virus ◽  
Hsv 1

Background: Epithelial cells play important roles as a critical barrier in protecting the cornea from microbial pathogens infection. Methods: In this study, we were aiming to investigate the role of E3 ubiquitin ligase tripartite motif protein 32 (TRIM32) in corneal epithelial cells in response to Herpes Simplex Virus type 1 (HSV-1) infection and to elucidate the underlying mechanisms. Results: We found the expression of TRIM32 was increased after infected with HSV-1 both in murine corneas and cultured human epithelial (HCE) cells. Furthermore, knockdown of the expression of TRIM32 significantly aggravated HSV-1 induced herpetic stromal keratitis (HSK) in mice and promoted the replication of HSV-1 in cultured HCE cells. We also observed that silencing of TRIM32 resulted in the decreased expression of IFN-β and suppressed activation of interferon regulatory factor 3 (IRF3) both in vivo and in vitro. Finally, we found TRIM32 positively regulate IFN-β production in corneal epithelial cells through promoting K63-linked polyubiquitination of stimulator of interferon genes (STING). Conclusion: In conclusion, our data suggested that TRIM32 as a crucial positive regulator of HSV-1 induced IFN-β production in corneal epithelial cells, and it played a predominant role in clearing HSV-1 from the cornea.

scholarly journals Activity and Mechanism of Action of N-Methanocarbathymidine against Herpesvirus and Orthopoxvirus Infections

2006 ◽  
Vol 50 (4) ◽  
pp. 1336-1341 ◽  
Author(s):  
Mark N. Prichard ◽  
Kathy A. Keith ◽  
Debra C. Quenelle ◽  
Earl R. Kern
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Mechanism Of Action ◽  
Type I ◽  
Viral Dna ◽  
Barr Virus ◽  
Epstein Barr ◽  
Simplex Virus

ABSTRACT N-Methanocarbathymidine [(N)-MCT] is a conformationally locked nucleoside analog that is active against some herpesviruses and orthopoxviruses in vitro. The antiviral activity of this molecule is dependent on the type I thymidine kinase (TK) in herpes simplex virus and also appears to be dependent on the type II TK expressed by cowpox and vaccinia viruses, suggesting that it is a substrate for both of these divergent forms of the enzyme. The drug is also a good inhibitor of viral DNA synthesis in both viruses and is consistent with inhibition of the viral DNA polymerase once it is activated by the viral TK homologs. This mechanism of action explains the rather unusual spectrum of activity, which is limited to orthopoxviruses, alphaherpesviruses, and Epstein-Barr virus, since these viruses express molecules with TK activity that can phosphorylate and thus activate the drug. The compound is also effective in vivo and reduces the mortality of mice infected with orthopoxviruses, as well as those infected with herpes simplex virus type 1 when treatment is initiated 24 h after infection. These results indicate that (N)-MCT is active in vitro and in vivo, and its mechanism of action suggests that the molecule may be an effective therapeutic for orthopoxvirus and herpesvirus infections, thus warranting further development.

Construction of a US3 lacZ insertion mutant of herpes simplex virus type 2 and characterization of its phenotype in vitro and in vivo

Virology ◽  
1992 ◽  
Vol 190 (1) ◽  
pp. 256-268 ◽  
Author(s):  
Yukihiro Nishiyama ◽  
Yoshinari Yamada ◽  
Ryutaro Kurachi ◽  
Tohru Daikoku
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Insertion Mutant ◽  
Simplex Virus

scholarly journals Herpes simplex virus type 2 virion host shutoff protein suppresses innate dsRNA antiviral pathways in human vaginal epithelial cells

2011 ◽  
Vol 92 (9) ◽  
pp. 1981-1993 ◽  
Author(s):  
Xiao-Dan Yao ◽  
Kenneth Lee Rosenthal
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Epithelial Cells ◽  
Herpes Simplex Virus Type ◽  
Innate Immune ◽  
Antiviral Responses ◽  
Virion Host Shutoff ◽  
Vaginal Epithelial Cells ◽  
Simplex Virus

Viruses that establish persistent infections have evolved numerous strategies to evade host innate antiviral responses. We functionally assessed the role of herpes simplex virus type 2 (HSV-2) virion host shutoff (vhs) protein on innate immune sensing pathways in human vaginal epithelial cells (VK2 ECs). Infection of cells with wild-type (WT) HSV-2 significantly decreased expression of innate immune sensors of viral infection, Toll-like receptor (TLR)2, TLR3, retinoic acid inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (Mda-5), relative to cells infected with a mutant that lacks vhs (vhsB) or mock-infected cells. Transfection with HSV-2 vhs similarly decreased expression of TLR2, TLR3, RIG-I and Mda-5, which was also confirmed in human embryonic kidney (HEK) 293 cells. vhsB infection of VK2 cells caused robust increases in the active form of interferon regulatory factor (IRF)3 and its translocation to the nucleus compared with the WT. Additionally, IRF3 activation by Sendai virus and polyinosinic : polycytidylic acid-induced stimulation of beta interferon (IFN-β) was significantly inhibited in vhs-transfected cells. Overall, our findings provide the first evidence that HSV-2 vhs plays roles in selectively inhibiting TLR3 and RIG-I/Mda-5, as well as TLR2-mediated antiviral pathways for sensing dsRNA and effectively suppresses IFN-β antiviral responses in human vaginal ECs.

scholarly journals Structural Variability of the Herpes Simplex Virus 1 GenomeIn VitroandIn Vivo

2012 ◽  
Vol 86 (16) ◽  
pp. 8592-8601 ◽  
Author(s):  
Charlotte Mahiet ◽  
Ayla Ergani ◽  
Nicolas Huot ◽  
Nicolas Alende ◽  
Ahmed Azough ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Considerable Proportion ◽  
Inverted Repeats ◽  
Herpes Simplex Virus 1 ◽  
Cell Extracts ◽  
Simplex Virus ◽  
Hsv 1

Herpes simplex virus 1 (HSV-1) is a human pathogen that leads to recurrent facial-oral lesions. Its 152-kb genome is organized in two covalently linked segments, each composed of a unique sequence flanked by inverted repeats. Replication of the HSV-1 genome produces concatemeric molecules in which homologous recombination events occur between the inverted repeats. This mechanism leads to four genome isomers (termed P, IS, IL, and ILS) that differ in the relative orientations of their unique fragments. Molecular combing analysis was performed on DNA extracted from viral particles and BSR, Vero, COS-7, and Neuro-2a cells infected with either strain SC16 or KOS of HSV-1, as well as from tissues of experimentally infected mice. Using fluorescence hybridization, isomers were repeatedly detected and distinguished and were accompanied by a large proportion of noncanonical forms (40%). In both cell and viral-particle extracts, the distributions of the four isomers were statistically equivalent, except for strain KOS grown in Vero and Neuro-2a cells, in which P and IS isomers were significantly overrepresented. In infected cell extracts, concatemeric molecules as long as 10 genome equivalents were detected, among which, strikingly, the isomer distributions were equivalent, suggesting that any such imbalance may occur during encapsidation.In vivo, for strain KOS-infected trigeminal ganglia, an unbalanced distribution distinct from the onein vitrowas observed, along with a considerable proportion of noncanonical assortment.

scholarly journals Activity of (+)-cyclaradine (Sch 31172) against herpes simplex virus in vitro and in vivo.

1987 ◽  
Vol 31 (1) ◽  
pp. 21-26 ◽  
Author(s):  
J Schwartz ◽  
M Ostrander ◽  
N J Butkiewicz ◽  
M Lieberman ◽  
C Lin ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Simplex Virus
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