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Phosphoinositide 3 kinase signalling may affect multiple steps during herpes simplex virus type-1 entry.
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PMID:  20810749     Owner:  NLM     Status:  MEDLINE    
Early interactions of herpes simplex virus type-1 (HSV-1) with cells lead to cytoskeletal changes facilitating filopodia formation and membrane fusion. Here, we demonstrate that phosphoinositide 3 kinase (PI3K) signalling may affect multiple steps during HSV-1 entry. An inhibitor of PI3K (LY294002) blocked HSV-1 entry and the blockage was cell-type- and gD receptor-independent. Entry inhibition was also observed with primary cultures of the human corneal fibroblasts and unrelated β- and γ-herpesviruses. Immunofluorescence analysis demonstrated that LY294002 negatively affected HSV-1-induced filopodia formation. Similar effects of the inhibitor were seen on HSV-1 glycoprotein-induced cell-to-cell fusion. Cells expressing HSV-1 glycoproteins (gB, gD, gH and gL) showed significantly less fusion with target cells in the presence of the inhibitor. Expression of a dominant-negative PI3K mutant negatively affected both entry and fusion. We also show that inhibition of PI3K signalling also affected RhoA activation required for HSV-1 entry into certain cell types.
Vaibhav Tiwari; Deepak Shukla
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-09-01
Journal Detail:
Title:  The Journal of general virology     Volume:  91     ISSN:  1465-2099     ISO Abbreviation:  J. Gen. Virol.     Publication Date:  2010 Dec 
Date Detail:
Created Date:  2010-11-18     Completed Date:  2010-12-13     Revised Date:  2014-09-10    
Medline Journal Info:
Nlm Unique ID:  0077340     Medline TA:  J Gen Virol     Country:  England    
Other Details:
Languages:  eng     Pagination:  3002-9     Citation Subset:  IM    
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MeSH Terms
Cell Fusion
Cells, Cultured
Chromones / metabolism
Enzyme Inhibitors / metabolism
Fibroblasts / virology
Herpesvirus 1, Human / physiology*
Microscopy, Fluorescence
Morpholines / metabolism
Organelles / drug effects
Phosphatidylinositol 3-Kinases / antagonists & inhibitors,  metabolism*
Signal Transduction*
Virus Internalization*
Grant Support
Reg. No./Substance:
0/Chromones; 0/Enzyme Inhibitors; 0/Morpholines; 154447-36-6/2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; EC 2.7.1.-/Phosphatidylinositol 3-Kinases

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Journal Information
Journal ID (nlm-ta): J Gen Virol
Journal ID (publisher-id): vir
ISSN: 0022-1317
ISSN: 1465-2099
Publisher: Society for General Microbiology
Article Information
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Copyright © 2010, SGM
Received Day: 3 Month: 6 Year: 2010
Accepted Day: 26 Month: 8 Year: 2010
Print publication date: Month: 12 Year: 2010
pmc-release publication date: Day: 1 Month: 12 Year: 2011
Volume: 91 Issue: Pt 12
First Page: 3002 Last Page: 3009
ID: 3052565
Publisher Id: 3002
DOI: 10.1099/vir.0.024166-0
PubMed Id: 20810749

Phosphoinositide 3 kinase signalling may affect multiple steps during herpes simplex virus type-1 entry
Vaibhav Tiwari1
Deepak Shukla12
1Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL 60612, USA
2Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
Correspondence: Correspondence: Deepak Shukla:
Present address: Department of Basic Medical Sciences, Colleges of Osteopathic Medicine and College of Optometry, Western University of Health Sciences, CA 91766, USA.

Herpes simplex virus type-1 (HSV-1) is a ubiquitous human virus, commonly associated with the outbreaks of facial cold sores. Recurrent infections in the eye can cause corneal blindness (Farooq et al., 2010). Severe complications especially in neonates and immunocompromised patients may result in retinitis and inflammation of the brain tissues that leads to encephalitis (Liesegang et al., 1989; reviewed by Liesegang, 2001; Roizman & Sears, 1996; Whitley et al., 1998). HSV-1 infects host cells through initial attachment to cells via surface heparan sulfate (HS) followed by fusion of the virion envelope with the plasma membrane (Shukla & Spear, 2001; Spear et al., 2000). The current model suggests that entry of virus requires four HSV glycoproteins (gB, gD, gH and gL) (Browne et al., 2001; Davis-Poynter et al., 1994; Forrester et al., 1992; Muggeridge, 2000; Pertel et al., 2001; Turner et al., 1998) and at least one cellular receptor for gD (Cocchi et al., 2000; Terry-Allison et al., 2001; Tiwari et al., 2004). The receptors for HSV-1 gD include a member of the tumour necrosis factor-receptor family named herpesvirus entry mediator (HVEM) (Montgomery et al., 1996; Tiwari et al., 2005a), a member of the immunoglobulin superfamily commonly known as nectin-1 (Cocchi et al., 1998; Shukla et al., 2006) and modifications in HS by multiple D-glucosaminyl 3-O-sulfotransferase (3-OST) isoforms. Among the known 3-OST isoforms, all but one (3-OST-1) isoforms mediate HSV-1 entry (O'Donnell et al., 2006; Shukla et al., 1999; Tiwari et al., 2005b; Xia et al., 2002; Xu et al., 2005) and cell-to-cell fusion (O'Donnell & Shukla, 2009; Tiwari et al., 2004). It has also been proposed that paired immunoglobulin-like receptor alpha can serve as a co-receptor for HSV-1 by interaction with glycoprotein B (gB) (Satoh et al., 2008; Shukla et al., 2009).

HSV can also induce host cell cytoskeletal rearrangements to facilitate infection (Akhtar & Shukla, 2009). In this regard, HSV-1 entry and cell-to-cell spread may particularly be benefitted by changes in cytoskeletal rearrangements (Farooq et al., 2010; Tiwari et al., 2008). For instance, cytoskeletal elements such as actin filaments may be reorganized in parallel bundles to form filopodia for viral surfing/transport to reach the cell body (O'Donnell & Shukla, 2008; Oh et al., 2010). Similarly, alterations in cytoskeleton may be needed when membranes fuse during HSV-1 entry or cell-to-cell spread (Spear et al., 2000; O'Donnell et al., 2010). In addition, HSV-1 also utilizes microtubules for transport from the cell periphery towards the nucleus (Marozin et al., 2004).

Recent studies have shown that HSV-1 relies heavily on actin cytoskeleton during phagoctyic-uptake by primary cultures of human corneal fibroblasts (CF) and for surfing in retinal pigment epithelial (RPE) cells (Clement et al., 2006; Tiwari et al., 2008). Induction of filopodia formation provides a unique large surface area for virus to surf and find the target cell (Oh et al., 2010). This mode of HSV-1 entry activates Rho-GTPase signalling pathways within a target cell that helps facilitate viral entry (Clement et al., 2006; Oh et al., 2010). It has been previously shown that Rho-GTPases (Rho-A and cdc42) are key modulators that facilitate filopodia formation during viral entry (Clement et al., 2006). One downstream signalling pathway for filopodia-induction is phosphoinositide 3 kinase (PI3K) (Greber, 2002). PI3Ks are a cellular family of heterodimeric enzymes that consist of a regulatory subunit (p85) activated by tyrosine phosphorylation, which recruits inositol phospholipids that are phosphorylated by the catalytic subunit (p110) (Carpenter et al., 1993; Hiles et al., 1992; Skolnik et al., 1991; Stoyanov et al., 1995). These lipids serve as second messengers that regulate the phosphorylation of other kinases such as Akt/PKB, cyclic AMP-dependent protein kinase A, some protein kinase C isoforms, and the ribosomal S6 kinases p70 and p85 (Coffer et al., 1998). The ability of PI3K to regulate multiple cellular pathways, coupled with the need for HSV to induce an environment favourable for viral entry via changes in actin cytoskeleton in host cells, prompted us to examine the role of PI3K signalling in HSV-1 entry into natural target cells from the human eye (Farooq et al., 2010). Our study demonstrates that PI3K activity is exploited by HSV-1 during filopodia induction and also during cell-to-cell fusion.

We began our study using HeLa, RPE and primary cultures of CF isolated from the stroma of human cornea (obtained from the Illinois Eye Bank, Chicago, IL, USA; processed by using the institution approved protocol in accordance with the Declaration of Helsinki). Human CF is a natural target cell type that has been shown to exploit 3-O-sulfated heparan sulfate as a receptor (Tiwari et al., 2006, 2007). RPE cells also get infected during a natural infection and virus entry is mediated by nectin-1 receptor (Tiwari et al., 2008). Cultures of CF were grown in L-glutamine containing minimum essential medium (MEM; Invitrogen) supplemented with 10 % FBS (Sigma) and 5 % calf serum (CS) as described previously (Yue & Baum, 1981). The transformed HeLa and RPE cells were grown in Dulbecco's modified Eagle medium (Invitrogen) containing 10 % FBS as described previously (Tiwari et al., 2008). The cells were trypsinized and passaged after reaching confluency. CFs from third passages were used for this study.

To determine the effect of the PI3K inhibitor (LY294002; Cell Signaling Technology) on HSV-1 entry, we first tested the ability of HSV-1 to infect cells in the presence and absence of LY294002. The inhibitor is stable at 37 °C and an extremely potent and specific inhibitor of PI3K activity (King et al., 1997; Wennstrom & Downward, 1999). HSV-1 entry into the cell was determined by using β-galactosidase-expressing HSV-1 reporter virus (KOS gL86). As shown in Fig. 1, the PI3K inhibitor significantly blocked viral entry in a dose-dependent manner in RPE, HeLa and CF cells. The blocking activity of the PI3K inhibitor was seen at concentrations as low as 0.05 mM as well. Interestingly, either pre-treatment of HSV-1 with the PI3K inhibitor or pre-treatment of cells showed similar results. This is probably not due to any virucidal effects of the inhibitor. Its well sustained cellular kinase inhibition activity is probably responsible for the inhibition of entry. The net concentration of the inhibitor does not change in either case as it has a relatively long half-life (3.5−10.0 h) (Gervais et al., 2006; Jones et al., 1999), which may cause the inhibitor to remain effective on cells regardless of whether the virus or the cells were treated first. The negative effect on entry was not associated with any particular gD receptor since the effect was repeatedly observed with each gD receptor expressed alone in Chinese hamster ovary (CHO-K1) cells (Fig. 1d), which do not normally express them (Shukla et al., 1999). We also evaluated whether the effect is limited to HSV-1 (KOS) strain or if other HSV-1 strains would also be negatively affected by the inhibitor. Nectin-1 expressing CHO Ig8 cells that express β-galactosidase upon viral entry (Montgomery et al., 1996) were used to examine additional virulent strains of HSV-1 (F, MP and 17) (Dean et al., 1994). The cells were pre-incubated with the PI3K inhibitor and then infected with various HSV-1 strains. The results from this experiment again showed that the inhibitor blocks entry of all HSV-1 strains in a dose-dependent manner (Fig. 1e). Next, to demonstrate that the inhibitory effect of LY294002 on HSV-1 entry was specific, we used a highly related compound LY303511 (Calbiochem Inc.) that does not affect PI3K activity. As shown in Fig. 1(f) the inactive compound had no effect on HSV-1 entry, while LY294002 significantly affected HSV-1 entry. A more potent PI3K signalling inhibitor wortmanin has also been shown to inhibit HSV-1 transport (Nicola & Straus, 2004). At this point we did not rule out that the effects seen on entry could have also been due to the inhibition of the capsid transport. The significance of PI3K signalling during HSV-1 entry was further ascertained by overexpressing a dominant-negative PI3K mutant lacking the p110-catalytic subunit-binding domain (ΔiSH2) (Ueki et al., 2000). This mutant significantly reduced viral entry into the cells (Fig. 1g), suggesting once again an important role for PI3K in HSV-1 entry.

We next investigated other herpesviruses and their dependence on PI3K signalling during entry. As shown in Fig. 2(a)–(c), pre-treatment of natural target cells with the PI3K inhibitor significantly reduced the entry of HSV-1 (α-herpesvirus), cytomegalovirus (CMV, Towne strain; β-herpesvirus) and human herpes virus-8 (HHV-8; γ-herpesvirus), suggesting that the effect of PI3K signalling may be universal among herpesviruses.

Further, to gain an understanding of the specific effects of the PI3K inhibitor, we asked whether the inhibitor can affect HSV-1-induced filopodia formation (Oh et al., 2010). To answer this question, immunofluorescence was used to stain wild-type HSV-1 (KOS)-infected HeLa and RPE cells in the presence and the absence of the inhibitor. As shown in Fig. 2(d) and (e), HSV-1 failed to induce filopodia in both types of cells pre-incubated with the PI3K inhibitor. This probably affects the entry, since the inability of cells to form filopodia has been shown to result in significant reduction of virus infectivity (Oh et al., 2010).

Finally, we tested the role of PI3K signalling during HSV-1 glycoproteins-mediated cell-to-cell fusion. Cell fusion has been used to demonstrate viral and cellular requirements during entry and spread (Pertel et al., 2001). Quite evidently, target cells expressing individual HSV-1 gD receptor nectin-1, HVEM and 3-OST-3 treated with the PI3K inhibitor demonstrated impaired cell-to-cell fusion with effector cells expressing four HSV-1 (KOS) glycoproteins, gB (pPEP98), gD (pPEP99), gH (pPEP100) and gL (pPEP101) (all plasmids described by Pertel et al., 2001) (Fig. 3a). This response was further confirmed by using a fluorescent-labelled cell fusion assay (Fig. 3b). Nectin-1-expressing target CHO-K1 cells co-transfected with pDSRed N1 fluorescent plasmid incubated with the PI3K inhibitor for 60 min failed to fuse with the effector CHO-K1 cells co-transfected with HSV-1 glycoprotein (gB, gD and gH–gL) and a GFP-expression plasmid [Fig. 3b(iii)]. In contrast, the control (untreated) effector red cells fused (yellow colour) with green target cells [Fig. 3b(i)]. Our result also shows the presence of filopodia on effector cells during cell fusion in the absence of inhibitor. It is clear that the inhibitor treatment not only blocks the cell fusion, but also negatively affects the induction of filopodia formation.

Finally, we rationalized that if PI3K regulates actin networks and induction of filopodia formation in HSV-1-infected cells then RhoA activation in human CF may also be affected by the inhibitor. This would be observed especially when PI3K is required upstream of RhoA activation. Our previous studies have shown that RhoA plays a critical role during phagoctyic uptake of HSV-1 by primary human CF (Clement et al., 2006) and likewise, it has been suggested that PI3K is involved in integrin-mediated signalling pathway that leads to the induction of filopodia (Chang et al., 2005). As shown in Fig. 3(c), pre-treatment of human CF with the PI3K inhibitor significantly reduced RhoA activation, which may also be a reason why HSV-1 activity is adversely affected by the inhibitor. The inhibitor blocks PI3K activity and RhoA activation by the virus may be downstream from it. The effect of the inhibitor on fusion was specific, since a highly related but inactive compound LY303511 (Calbiochem Inc.) had no significant effect on HSV-1 glycoprotein-induced cell fusion with target CF cells (Fig. 3d). In addition, expression of the dominant-negative PI3K mutant (ΔiSH2) (Ueki et al., 2000) in target CF cells also inhibited HSV-1 glycoprotein-induced cell fusion (Fig. 3e). Collectively, our results suggest an important role for PI3K in membrane fusion.

The role of actin cytoskeleton is widely implicated in microbial pathogenesis (Dohner & Sodeik, 2005; Greber & Way, 2006; Marsh & Helenius, 2006). Multiple viruses exploit the host actin cytoskeleton to facilitate important aspects of their life cycles including entry into target cell, egress and intercellular spread (Radtke et al., 2006). Recent findings indicate that murine leukemia virus (MLV), African swine fever virus and human papillomavirus use filopodia to infect cells (Jouvenet, et al., 2006; Lehmann et al., 2005; Sherer et al., 2007; Smith et al., 2008). Similarly, Kaposi's sarcoma herpes virus enhances filopodia formation (Veettil et al., 2006). Even before entering into cells, viruses interact with the actin cytoskeleton in a number of ways. Recent live-cell imaging results have demonstrated a role for the actin cytoskeleton in virus entry via the process of ‘surfing’. In this process the retroviruses, MLV and avian leukosis virus, as well as vesicular stomatitis virus, were shown to associate with the dense microvilli and/or filopodia of polarized epithelia and move on to the cell surface in an actin- and myosin-dependent manner prior to internalization (Lehmann et al., 2005; Sherer et al., 2007). Others have shown that blockage of PI3K signalling induced by additional viruses such as human immunodeficiency virus inhibits viral infection (François & Klotman, 2003). Thus, PI3K signalling and its downstream effectors may play a vital role in supporting virus infections in general (Dimitrov, 2004; Sieczkarski & Whittaker, 2005). Our study opens the door for future studies analysing specific viral and cellular mediators of PI3K activation by HSV-1. Knowledge of such specific mediators is likely to open up new ways to develop anti-herpesvirus agents and strategies.

Human CF and human conjunctival epithelial cells were kindly provided by Dr Beatrice Yue (Loins of Illinois Eye Research Institute, University of Illinois, Chicago, USA) and Dr Ilene Gipson (Harvard Medical School, USA). This work was supported by NIH grants AI057860 (D. S), AI081869 (D. S.) and a Core Grant EY01792. D. S. is a recipient of the Lew Wasserman Merit award from Research to Prevent Blindness (RPB). V. T. was supported by an Institutional Research Grant (WUHS no. N12587). We sincerely thank Dr Kahn C. Ronald (Harvard Medical School, USA) for providing us the PI3K dominant-negative constructs.

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