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Journal of Virology, April 2005, p. 4540-4544, Vol. 79, No. 7
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.7.4540-4544.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Herpes Simplex Virus Entry Mediator Associates in Infected Cells in a Complex with Viral Proteins gD and at Least gH

Pilar Perez-Romero,1 Aleida Perez,1 Althea Capul,1 Rebecca Montgomery,2 and A. Oveta Fuller3*

Department of Microbiology and Immunology,1 Program in Cellular and Molecular Biology, School of Medicine, University of Michigan, Ann Arbor, Michigan,3 Institute for Molecular Virology, University of Wisconsin, Madison, Wisconsin2

Received 18 June 2004/ Accepted 19 October 2004


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ABSTRACT
 
We examined herpes simplex virus (HSV)-infected human HEp-2 cells or porcine cells that express herpes virus entry mediator (HVEM) for virus and receptor protein interactions. Antibody to HVEM, or its viral ligand gD, coimmunoprecipitated several similar proteins. A prominent 110-kDa protein that coprecipitated was identified as gH. The HVEM/gD/gH complex was detected with mild or stringent cell lysis conditions. It did not form in cells infected with HSV-1(KOS)Rid1 virus or with null virus lacking gD, gH, or gL. Thus, in cells a complex forms through physical associations of HVEM, gD, and at least gH.


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TEXT
 
Herpes simplex virus (HSV) enters into cells through attachments that lead to fusion of the virus envelope with the plasma membrane (12). This involves multiple virus envelope and host cell proteins (reviewed in reference 29). Herpes virus entry mediator (HVEM or HveA), isolated because it mediated HSV-1(KOS) entry into Chinese hamster ovary (CHO) cells (22), is a member of the tumor necrosis factor receptor family that binds protein ligands lymphotoxin-{alpha} and LIGHT (13, 28). Biochemical analyses in vitro indicate that HVEM binds to soluble forms of glycoprotein D (gD) of HSV (4, 6, 7, 37). Several structural studies map the amino acid contacts of purified gD when it is bound to HVEM (4, 6, 7, 37, 38). However, what occurs in cells has not been determined.

How HSV glycoproteins bind cellular receptors to lead to pH-independent infection of susceptible cells is not yet clear. Binding of a viral ligand such as gD to a cellular attachment receptor, such as HVEM, is required for stable attachment and to alter protein conformation for events of entry (5, 25, 28).

The HSV envelope contains at least 10 integral membrane glycoproteins (29). Their organization in the virus envelope and interactions among the glycoproteins and with cell receptors during infection are actively investigated (14, 20, 23, 25, 28, 31, 34, 36). Reports in the literature differ regarding the physical interactions detected among HSV glycoproteins (14, 15, 26). Handler et al. found homo- and hetero-oligomeric complexes of viral envelope proteins from cross-linking of purified virions or virus exposed to cells (14, 15). However, others found no evidence of complex formation among the essential glycoproteins gB, gD, and gH/gL in virions (26).

To further explore HSV receptors and viral proteins during infection, we took advantage of porcine cells that were previously well characterized as poorly susceptible to HSV due to the lack of a stable attachment receptor (25, 32). They provide a highly tractable system to explore interactions of HSV with individual or combinations of entry receptors. The porcine cell line SK6-A7 was stably transformed to constitutively express human HVEM (22). HVEM RNA was detected by reverse transcription-PCR (Fig. 1A). HVEM protein was detected in the cell surface by fluorescence-activated cell sorting (FACS) using polyclonal antibodies R-140 and R-95 made against a truncated HVEM, 200tHVEM (Fig. 1E to H). As shown with HB1-9 as one representative cell line, all porcine cells that expressed HVEM allowed HSV entry (Fig. 1B to D), infection, binding, and spread (data not shown).



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  		FIG. 1. HVEM expression in porcine cells. (A) HVEM mRNA amplified by reverse transcription-PCR. (B to D) Porcine HB19 cells, as one representative cell line, transformed to express HVEM protein, and Neo (empty-plasmid-transformed) cells exposed to HSV-1(SCgHZ)lacZ+ at 10 PFU/cell. Cells were fixed and X-Gal (5-bromo-4-chloro-3-indolyl-ß-D-galactopyranoside) stained for ß-galactosidase protein. Photographs were taken at a magnification of x40 with an inverted microscope. The monolayer was completely infected by 8 h (B) and mostly destroyed by 24 h (C). (E to H) Cell surface HVEM detected by FACS. Monolayers were incubated at 4°C for 30 min with anti-HVEM (R-140) (arrowheads), preimmune serum (gray), or no primary antibody (black). Cells were examined by FACS after 30 min of incubation with anti-rabbit conjugated fluorescein isothiocyanate. Panel H shows histograms of HVEM porcine cells with overlap for HB1-9 and HA1-5 (*).

Several approaches with isolated proteins, including a three-dimensional structure of purified HVEM and gD (4), show that HVEM can bind to gD. To examine interactions during infection, 35S-radiolabeled lysates of mock- or HSV-infected cells were solubilized in E1A lysis buffer (50 mM HEPES, 250 mM NaCl, 0.1% NP-40) and immunoprecipitated with antibodies to gD (I-99-1 or II-436) or HVEM (R-140 or R-95) (Fig. 2). Several proteins that were prominent in immunoprecipitations from infected HB1-9 and HEp-2 cells. Cells were not present in entry-defective Neo cells. Cells exposed to virus- or mock infected were analyzed (Fig. 2A). Antibodies for either gD or HVEM immunoprecipitated a 60-kDa protein identified as gD by the location of radiolabeled protein and by Western blotting using polyclonal antibody to gD (R-18). This was found for infected human HEp-2 and porcine HB1-9 cells but not for Neo or mock-infected cells (Fig. 2A, B, and E). Confirmation of gD in lysates immunoprecipitated with rabbit polyclonal anti-HVEM (R-140) was hampered by recognition of rabbit immunoglobulin that migrates near the 60-kDa size of gD (data not shown). However, associations of gD and HVEM from infected cells are in agreement with numerous reports from in vitro studies that show gD binding to HVEM (4, 6, 7, 36, 37).



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  		FIG. 2. Immunoprecipitation to examine viral and cellular proteins. Human HEp-2 or porcine HB1-9 or Neo cells are mock (–) or HSV-1(F) (+) infected at 3 PFU/cell. (A) 35S-radiolabeled immunoprecipitated proteins were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography. Antibodies used for immunoprecipitations are indicated in the key (17, 24). Closed arrowheads indicate the location of gD. Open arrows point to prominent bands found only in infected cells lysates. Top open arrow, a prominent 110-kDa protein coprecipitated with either of the antibodies for gD or HVEM. (B to F) For Western blotting of unlabeled immunoprecipitated samples, proteins transferred to nitrocellulose were analyzed using polyclonal anti-gD, R-18 (B, E) (12), or anti-gH, R-83 (C to D, F) (26). (B to D) Cell lysates were made using E1A buffer for mild lysis conditions. (E to F) Cell lysates using a more-stringent buffer included 50 mM Tris-HCl (pH 7.5), 100 mM NaCl, 1% NP-40, and 0.5% sodium deoxycholate. IP, immunoprecipitation.

A prominent 110-kDa protein coprecipitated with either of the antibodies for gD or HVEM (Fig. 2A). It was recognized as gH by Western blotting using polyclonal antibody to gH (R-83) (Fig. 2C to D and F). A less prominent band of 35-kDa not recognized in Western blotting as gD, gH, or gC might be a viral product, since it was only detected in infected cell lysates. Although R-140 and R-95 recognized purified 200tHVEM, location of HVEM was not possible since neither detected HVEM in cell lysates by Western blotting.

These results indicated that gD and gH can coprecipitate with antibodies to HVEM or gD. They suggest an association of gD, HVEM, and at least gH in HSV-infected cells.

To determine if the relatively mild E1A lysis buffer was responsible for retaining protein interactions, cells were lysed and washed with a higher-detergent-content buffer (50 mM Tris-HCl [pH 7.5], 100 mM NaCl, 1% NP-40, 0.5% sodium deoxycholate) designed for HSV glycoprotein analyses (16, 30, 39). Immunoprecipitations also included antibody to gH (52S). Protein identities were confirmed by Western blotting (Fig. 2E and F). Under both cell lysis conditions, a complex that contains HVEM/gD/gH is detected in infected human cells or susceptible porcine cells containing HVEM as a stable attachment receptor. This agrees with in vitro binding of gD to HVEM and with HSV entry that involves stable binding required for infection (4, 6, 7, 18, 25, 35, 36). The fact that neither anti-gH antibody 52S (Fig. 2E and F) nor 53S (data not shown) coprecipitated gD suggested that epitopes recognized by the antibodies might overlap the domains of gH that interact with gD or HVEM. Alternatively, gH conformation may be altered in the complex.

To examine the specificity of the immunoprecipitations or possible trapping of gH, we used control antibodies to gC (II-73-3), an HSV glycoprotein that binds to heparan sulfate (Fig. 3), a monoclonal antibody to the HSV capsid protein VP5 (8F5), or a rabbit preimmune serum for R-95 (Fig. 4A to B). Western blotting showed that antibody to gD (I-99-1) brought down gD and gH, but not gC, from infected cells (Fig. 3A and C). gC was not detected in immunoprecipitations performed with antibody to gD or gH (Fig. 3C). Antibody to gC immunoprecipitated only gC (Fig. 3A to C).



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  		FIG. 3. Western blotting to examine the presence of other HSV glycoproteins in immunoprecipitations. HEp-2 or HB1-9 cells infected with HSV-1(F) (+) or mock infected (–) were lysed with E1A buffer and proteins were immunoprecipitated and analyzed by Western blotting (A to C). Immunoprecipitations were with the monoclonal antibodies in the key. Western blotting of immunoprecipitated unlabeled proteins used polyclonal antibody (A) R-18, anti-gD, (B) R-83, anti-gH, or (C) R-47, anti gC. Lysates of HSV-1(F)-infected cell lysates without immunoprecipitation were used as a control for Western detection of the HSV glycoproteins (positive control) (A to C). Molecular weight markers are indicated. IP Ab, immunoprecipitation antibody.



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  		FIG. 4. Immunoprecipitations to examine proteins in infection with HSV-1(F) or mutant viruses. (A and B) HEp-2 cells infected at 10 PFU/cell with HSV-1(F) or Rid1 (8) or mock infected. (C-D) HB19 cells infected at 10 PFU/cell with phenotypically complemented HSV-1(FgDß) ({Delta}gD –/+) (19), HSV-1(KOS) SCgHZ ({Delta}gH –/+) (9), or HSV-1(KOS)gL86 ({Delta}gL –/+) (27). (A, C) Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of immunoprecipitated 35S-radiolabeled protein lysates using the same conditions as in Fig. 3. Antibodies for immunoprecipitation are indicated in the key. (B, D) Western blots of unlabeled immunoprecipitated proteins were performed in parallel and analyzed with polyclonal antibody anti-gH (R-83) or anti-gD (R-18). Lysates of HSV-1(F)-infected HEp-2 cells were used as a control for the presence of HSV glycoproteins (positive control).

Antibodies to VP5 (8F5) precipitated only VP5 from HEp-2 cells infected with HSV-1(F) or a gD mutant Rid1 (8) but not from mock-infected cells (Fig. 4A). Rabbit preimmune sera, which contains Fc binding regions that might interact with the gE/gI complex of HSV, brought down a number of nonspecific high-molecular-weight proteins found in both mock and infected cell lysates. Western analyses showed that this material did not contain gD or gH (Fig. 4A and B). We conclude that gD and gH coprecipitated specifically and were not merely trapped nonspecifically in a protein-antibody complex.

In a different approach to explore the composition and specificity of the HVEM/gD/gH complex, susceptible cells were exposed to viruses that had a point mutation in gD (Rid1) (8, 22) or that lacked gD, gH, or gL (2, 9, 19, 27). The Rid1 mutant does not infect CHO, BHK, or porcine cells when HVEM is present as the only human receptor protein for HSV entry (8, 18). This is due to a point mutation at amino acid 27 in gD that affects interaction with HVEM. Rid1 can bind and infect HEp-2 cells that have other receptors for HSV.

From Rid1-infected HEp-2 cell lysates, antibody to gD or to gH immunoprecipitated individual gD or gH, respectively (Fig. 4A and B). However, Western blotting showed no coprecipitation (Fig. 4B). The HVEM/gD/gH complex did not form with Rid1 virus-infected cells. This shows a dependence of interactions on associations of HVEM and wild-type gD that do not occur in the presence of Rid1 mutant gD. This also indicates that the specificity of HVEM, gD, and gH interact specifically in the complex in infected cells.

Because gH is found in a heterodimer of gH/gL (27), the presence of gL might be expected in the complex. Since gL antibody for Western blotting was not available, we used complemented null mutant viruses as one approach to examine the influence of the absence of gD, gH, or gL on the complex. Phenotypically complemented gD, gH, or gL mutant viruses infected susceptible cells. However, the genotypically null gD, gH, or gL viruses produced no newly synthesized gD, gH, or gL in infected cells (Fig. 4C and D) (2, 9, 19, 27).

From mutant virus-infected HB19 and HEp-2 cells (data not shown), antibody to gD immunoprecipitated only gD (Fig. 4C and D). In the absence of gL, neither gD nor gH proteins coprecipitated in a complex, even with antibody to gD. These results indirectly suggested that gL performs a role in the HVEM/gD/gH complex interactions. This role may be in the trafficking of gH or by direct gL interactions with a protein in the complex.

Hetero-oligomerization of HSV glycoproteins has been an unresolved issue. Immunogold electron microscopy of purified HSV particles could not locate gH in the virion envelope but located gB, gC, and gD as three visually distinct structures (31, 33). Rodger et al. found no evidence of hetero-oligomeric complex during glycoprotein incorporation into the HSV envelope (26) and concluded that assembly of glycoproteins into virions is independent of the presence of individual gB, gC, gD, or gH proteins.

Evidence that HSV glycoproteins may form high-order complexes came from chemical cross-linking studies (14, 40). Cross-linked proteins from purified virions revealed homo-oligomers of the same viral glycoproteins and also hetero-oligomers of different HSV glycoproteins. Different patterns from chemical cross-linking during virus penetration suggested that composition of cross-linked hetero-oligomers among the viral envelope glycoproteins can be altered by the events of virus penetration.

The results reported here are consistent with and reconcile each of these previous findings. Formation of a HVEM/gD/gH complex may require the presence of a cellular receptor. Therefore, hetero-complexes would not be found when purified virions are examined by electron microscopy. Detected interactions of gD and the gH/gL heterodimer with each other or with their respective cell receptors could be transient during entry or could form after de novo protein synthesis in infected cells. The interactions are consistent with what is known about viral glycoprotein and receptor requirements for HSV infection and with models of predicted events in its pH-independent entry, spread, or viral-induced membrane fusion (1, 3, 10, 11, 21, 29). We detected associations of gD and gH in infected human cells and also in infected HVEM-expressing porcine cells where there is at least one human cellular receptor for HSV. The interaction of gD and at least gH in a receptor complex is consistent with predicted functions of HSV glycoproteins that are required to mediate events of membrane fusion at virus spread or entry.

(Parts of this research were performed in completion of Ph.D. requirements for A.P.)


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ACKNOWLEDGMENTS
 
We thank researchers in the field for generosity with antibodies and mutant virus strains. We thank Patricia Spear and Malini Raghavan for helpful discussions.

We thank the University of Michigan Rackham Graduate School for fellowships for A.P. and P.P.-R., the University of Michigan Biophysics Program for an undergraduate summer research award to A.P., and NIAID for grants to A.O.F.


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FOOTNOTES
 
* Corresponding author. Mailing address: 6736 Medical Sciences II, University of Michigan, Ann Arbor, MI 48109-0620. Phone: (734) 647-3830. Fax: (734) 764-3562. E-mail: fullerao{at}umich.edu. Back


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Journal of Virology, April 2005, p. 4540-4544, Vol. 79, No. 7
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.7.4540-4544.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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  • Gianni, T., Amasio, M., Campadelli-Fiume, G. (2009). Herpes Simplex Virus gD Forms Distinct Complexes with Fusion Executors gB and gH/gL in Part through the C-terminal Profusion Domain. J. Biol. Chem. 284: 17370-17382 [Abstract] [Full Text]  
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