Dynasore Disrupts Trafficking of Herpes Simplex Virus Proteins

Mues, Mascha B.; Cheshenko, Natalia; Wilson, Duncan W.; Gunther-Cummins, Leslie; Herold, Betsy C.

doi:10.1128/jvi.00636-15

Cited by 24 publications

(21 citation statements)

References 39 publications

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“…HSV-2 tended to be distributed in the area near or within the cell nuclei in the virus control or acyclovir-treated cells, whereas it was distributed in the periphery area around the cell membranes in Retro-2.1-or chloroquine-treated cells, indicating that Retro-2.1 and chloroquine inhibited HSV-2 entry into the cells. Therefore, Retro-2.1 was demonstrated to block HSV-2 entry into host cells as previously reported in a study on the inhibitory effect of Dynasore on HSV-2 entry rather than binding [36].…”

Section: Retro-21 Blocks Hsv-2 Entry Into Cellssupporting

confidence: 73%

“…Vero cells were seeded in 24-well plates to 90% confluency and treated as previously reported in a study on effects of Dynasore on HSV-2 binding and entry [36]. Briefly, the cells were treated with 12.5 μM Retro-2.1 at 37°C for 5 h before infection, or with 15 μM chloroquine or 1 μM acyclovir for 5 h before or at the same time with infection.…”

Section: Binding and Entry Assaysmentioning

confidence: 99%

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Antiviral Effect of Retro-2.1 against Herpes Simplex Virus Type 2 In Vitro

Dai

et al. 2018

Journal of Microbiology and Biotechnology

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could inhibit HSV-2 infection, with 50% inhibitory concentrations of 5.58 µM and 6.35 µM in cytopathic effect inhibition and plaque reduction assays, respectively. The cytotoxicity of Retro-2.1 was relatively low, with a 50% cytotoxicity concentration of 116.5 µM.We also preliminarily identified that Retro-2.1 exerted the antiviral effect against HSV-2 by a dual mechanism of action on virus entry and late stages of infection. Therefore, our study for the first time demonstrated Retro-2.1 as an effective antiviral agent against HSV-2 in vitro with targets distinct from those of nucleoside analogs.Keywords: Herpes simplex virus type 2, Retro-2.1, antiviral effect, entry, late stage, vesicle transport 850 Dai et al. J. Microbiol. Biotechnol.

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Section: Retro-21 Blocks Hsv-2 Entry Into Cellssupporting

confidence: 73%

Section: Binding and Entry Assaysmentioning

confidence: 99%

Antiviral Effect of Retro-2.1 against Herpes Simplex Virus Type 2 In Vitro

Dai

et al. 2018

Journal of Microbiology and Biotechnology

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“…evaluated dynasore, a small-molecule inhibitor of dynamin, on HSV-1 and HSV-2 life cycle. Dynasore affected virus entry, trafficking of viral proteins and capsid formation of HSV-1 and HSV-2 (182). Cheshenko et al.…”

Section: New Developments In Antiherpesvirus Treatment: What's the Nementioning

confidence: 99%

Distribution and effects of amino acid changes in drug-resistant α and β herpesviruses DNA polymerase

Topalis¹,

Gillemot²,

Snoeck³

et al. 2016

Nucleic Acids Res

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Emergence of drug-resistance to all FDA-approved antiherpesvirus agents is an increasing concern in immunocompromised patients. Herpesvirus DNA polymerase (DNApol) is currently the target of nucleos(t)ide analogue-based therapy. Mutations in DNApol that confer resistance arose in immunocompromised patients infected with herpes simplex virus 1 (HSV-1) and human cytomegalovirus (HCMV), and to lesser extent in herpes simplex virus 2 (HSV-2), varicella zoster virus (VZV) and human herpesvirus 6 (HHV-6). In this review, we present distinct drug-resistant mutational profiles of herpesvirus DNApol. The impact of specific DNApol amino acid changes on drug-resistance is discussed. The pattern of genetic variability related to drug-resistance differs among the herpesviruses. Two mutational profiles appeared: one favoring amino acid changes in the Palm and Finger domains of DNApol (in α-herpesviruses HSV-1, HSV-2 and VZV), and another with mutations preferentially in the 3′-5′ exonuclease domain (in β-herpesvirus HCMV and HHV-6). The mutational profile was also related to the class of compound to which drug-resistance emerged.

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“…The large GTPase dynamin assembles into helical polymers at the necks of budding vesicles and catalyzes membrane fission and fusion (20)(21)(22). The role of dynamin during HSV-1 internalization is still controversial and seems to depend on the cell type and entry pathway (16)(17)(18)23). We found a dynamin-dependent uptake of HSV-1 in keratinocytes and dermal fibroblasts but not in primary hippocampal neurons (9,15).…”

mentioning

confidence: 70%

Herpes Simplex Virus 1 Can Enter Dynamin 1 and 2 Double-Knockout Fibroblasts

Möckel

Rahn

Cruz

et al. 2019

J Virol

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Dynamin GTPases, best known for their role in membrane fission of endocytic vesicles, provide a target for viruses to be exploited during endocytic uptake. Recently, we found that entry of herpes simplex virus 1 (HSV-1) into skin cells depends on dynamin, although our results supported that viral internalization occurs via both direct fusion with the plasma membrane and via endocytic pathways. To further explore the role of dynamin for efficient HSV-1 entry, we utilized conditional dynamin 1 and dynamin 2 double-knockout (DKO) fibroblasts as an experimental tool. Strikingly, HSV-1 entered control and DKO fibroblasts with comparable efficiencies. For comparison, we infected DKO cells with Semliki Forest virus, which is known to adopt clathrin-mediated endocytosis as its internalization pathway, and observed efficient virus entry. These results support the notion that the DKO cells provide alternative pathways for viral uptake. Treatment of cells with the dynamin inhibitor dynasore confirmed that HSV-1 entry depended on dynamin in the control fibroblasts. As expected, dynasore did not interfere with viral entry into DKO cells. Electron microscopy of HSV-1-infected cells suggests viral entry after fusion with the plasma membrane and by endocytosis in both dynaminexpressing and dynamin-deficient cells. Infection at low temperatures where endocytosis is blocked still resulted in HSV-1 entry, although at a reduced level, which suggests that nonendocytic pathways contribute to successful entry. Overall, our results strengthen the impact of dynamin for HSV-1 entry, as only cells that adapt to the lack of dynamin allow dynamin-independent entry. IMPORTANCE The human pathogen herpes simplex virus 1 (HSV-1) can adapt to a variety of cellular pathways to enter cells. In general, HSV-1 is internalized by fusion of its envelope with the plasma membrane or by endocytic pathways, which reflects the high adaptation to differences in its target cells. The challenges are to distinguish whether multiple or only one of these internalization pathways leads to successful entry and, furthermore, to identify the mode of viral uptake. In this study, we focused on dynamin, which promotes endocytic vesicle fission, and explored how the presence and absence of dynamin can influence viral entry. Our results support the idea that HSV-1 entry into mouse embryonic fibroblasts depends on dynamin; however, depletion of dynamin still allows efficient viral entry, suggesting that alternative pathways present upon dynamin depletion can accomplish viral internalization.

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Dynasore Disrupts Trafficking of Herpes Simplex Virus Proteins

Cited by 24 publications

References 39 publications

Antiviral Effect of Retro-2.1 against Herpes Simplex Virus Type 2 In Vitro

Antiviral Effect of Retro-2.1 against Herpes Simplex Virus Type 2 In Vitro

Distribution and effects of amino acid changes in drug-resistant α and β herpesviruses DNA polymerase

Herpes Simplex Virus 1 Can Enter Dynamin 1 and 2 Double-Knockout Fibroblasts

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