Variability of Herpes Simplex Virus 1 gL and Anti-gL Antibodies That Inhibit Cell Fusion but Not Viral Infectivity

Novotny, Maria; Parish, Mary Lynn; Spear, Patricia G.

doi:10.1006/viro.1996.0347

Cited by 47 publications

(54 citation statements)

References 2 publications

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“…mAbs H170 to gD, H1817 to gB, and H633 to gC were from the Goodwin Institute (Plantation, FL). pAb R8 to gD (43), pAb ZC15 to gD C-tail (44), pAb R95 and pAb R140 to HVEM (34,45), mAb VII.62.15 to gL (46), H12 (47), and CK4, CK9, and CK35 (35) have been described.…”

Section: Methodsmentioning

confidence: 99%

RETRACTED: The herpesvirus glycoproteins B and H·L are sequentially recruited to the receptor-bound gD to effect membrane fusion at virus entry

Gianni

Forghieri²,

Campadelli-Fiume³

2006

Proc. Natl. Acad. Sci. U.S.A.

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Four glycoproteins (gD, gB, gH, and gL) are required for herpes simplex virus entry into the cell or for cell–cell fusion in transfected cells. gD serves as the receptor-binding glycoprotein and as the trigger of fusion; the other three execute fusion between the viral envelope and the plasma and endocytic membranes or the membranes of adjacent cells and are highly conserved among members of the herpesvirus family. Details of the interaction of gD with gB, gH, and gL were not known. Here, we report that the four glycoproteins assemble into a complex initiated by the interaction of gD with its cellular receptor. gB is recruited to the gD–receptor complex next, even in the absence of gH·gL. gH·gL is recruited next, but only to the receptor–gD–gB ensemble. A complex with the composition receptor–gD–gB–gH·gL is assembled transiently with a life span of 15–30 min in cells exposed to virus but can also be found in infected cells and in cells committed to form polykaryocytes after transfection of the glycoprotein quartet. The results indicate that the complex assembly is a critical step in the process of virus entry and fusion, and that no viral protein other than those that participate in the complex itself is required for complex assembly. These findings imply critical protein–protein interactions among the quartet as herpes simplex virions enter the cells and at cell–cell fusion, define a specific order of recruitment, and place gH·gL as the last link in the process of glycoprotein recruitment to the complex.

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Section: Methodsmentioning

confidence: 99%

RETRACTED: The herpesvirus glycoproteins B and H·L are sequentially recruited to the receptor-bound gD to effect membrane fusion at virus entry

Gianni

Forghieri²,

Campadelli-Fiume³

2006

Proc. Natl. Acad. Sci. U.S.A.

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“…It is not clear at present whether gL has a role in hemifusion other than to ensure the appropriate folding and localization of gH. mAbs to HSV-1 gL can block cell-cell fusion but not virus entry, suggesting that gL may be directly involved in the fusion process (48). However, all gL mutants that mediate gH trafficking out of the endoplasmic reticulum also mediate membrane fusion, and no mutant has yet been isolated that mediates gH trafficking to the cell surface and fails to function in fusion (13,49,50).…”

Section: Discussionmentioning

confidence: 99%

Herpes simplex virus type 1 mediates fusion through a hemifusion intermediate by sequential activity of glycoproteins D, H, L, and B

Subramanian

Geraghty

2007

Proc. Natl. Acad. Sci. U.S.A.

158

145

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Virus-induced membrane fusion can be subdivided into three phases defined by studies of class I and class II fusion proteins. During Phase I, two membranes are brought into close apposition. Phase II marks the mixing of the outer membrane leaflets leading to formation of a hemifusion intermediate. A fusion pore stably forms and expands in Phase III, thereby completing the fusion process. Herpes simplex virus type 1 (HSV-1) requires four glycoproteins to complete membrane fusion, but none has been defined as class I or II. Therefore, we investigated whether HSV-1-induced membrane fusion occurred following the same general phases as those described for class I and II proteins. In this study we demonstrate that glycoprotein D (gD) and the glycoprotein H and glycoprotein L complex (gHL) mediated lipid mixing indicative of hemifusion. However, content mixing and full fusion required glycoprotein B (gB) to be present along with gD and gHL. Our results indicate that, like class I and II fusion proteins, fusion mediated by HSV-1 glycoproteins occurred through a hemifusion intermediate. In addition, both gB and gHL are probably directly involved in the fusion process. From this, we propose a sequential model for fusion via HSV-1 glycoproteins whereby gD is required for Phase I, gHL is required for Phase II, and gB is required for Phase III. We further propose that glycoprotein H and gB are likely to function sequentially to promote membrane fusion in other herpesviruses such as Epstein-Barr virus and human herpesvirus 8.lipid transfer ͉ membrane fusion ͉ fluorescence microscopy S tudies using class I and class II fusion proteins have demonstrated that virus-induced membrane fusion can be subdivided into three phases (1, 2). Phase I involves bringing opposing membranes into close proximity through a viral glycoprotein binding a cellular receptor. Phase II involves the initiation of lipid mixing between the two apposed membranes and is completed when the outer membrane leaflets are mixed to form an intermediate called hemifusion. Phase III begins when the inner membrane leaflets are mixed and continues the pore formation and expansion. The completion of Phase III signifies the completion of the fusion process. The three phases of membrane fusion (close apposition, hemifusion, and complete fusion) are useful to characterize functions of viral glycoproteins in the fusion process (1, 3, 4). Fusion proteins that have Phase I function bring membranes in close apposition and ultimately result in the initiation of the fusion process. Fusion proteins that have Phase II function are capable of mixing outer membrane leaflets leading to hemifusion. Phase III fusion proteins are capable of forming and expanding a fusion pore. For many viruses, one or two fusion proteins can carry out all phases of membrane fusion. The fusion process has yet to be characterized for viruses that require more than two fusion glycoproteins, and a major issue is whether multiple glycoproteins mediate fusion through a hemifusion intermediate.Herpes simplex ...

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“…Antibody reagents specific for gL have been described that had an inhibitory effect on virus infectivity and cell fusion (Klupp et al, 1997 ;Novotny et al, 1996 ;Peng et al, 1998). Like gH mutant viruses, gL deletion mutants were also defective for penetration in vitro (Klupp et al, 1997 ;Roop et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

“…Like gH mutant viruses, gL deletion mutants were also defective for penetration in vitro (Klupp et al, 1997 ;Roop et al, 1993). HSV-1 gL antibody reactivity was mapped to the C terminus, implying a role for this region in fusion (Novotny et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

N- and C-terminal external domains of human herpesvirus-6 glycoprotein H affect a fusion-associated conformation mediated by glycoprotein L binding the N terminus.

Anderson

Gompels

1999

Journal of General Virology

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Human herpesvirus-6 (HHV-6), like other betaherpesviruses, shows cell fusion with wild-type strains, and this cellular spread is mediated by the glycoprotein gH/gL complex. Anti-fusion monoclonal antibodies (MAbs) specific for HHV-6 glycoprotein gH inhibit infection and prevent cellular spread by syncytia formation. Reactivity of these MAbs with gH deletion mutants suggests a conserved C-terminal fusion-associated domain. A conserved motif here has an N-glycosylation site and characteristics of a beta turn. Motif deletion abrogated MAb recognition while coexpression with glycoprotein gL restored this conformational epitope, indicating the importance of folding and not glycosylation at this site. Our previous studies showed gL binding to gH at an Nterminal domain specific for betaherpesviruses. To further examine the function of this N-terminal domain, a betaherpesvirus-specific motif was deleted. This mutant gH still bound gL, and was recognized by the anti-fusion MAbs ; however, recognition was now primarily in the immature form and reduced during processing to the mature form. A model is discussed whereby gL binding gH at the N-terminal domain acts to draw together the C-terminal extracellular domain and this interaction affects a functional conformation during glycoprotein maturation.

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Variability of Herpes Simplex Virus 1 gL and Anti-gL Antibodies That Inhibit Cell Fusion but Not Viral Infectivity

Cited by 47 publications

References 2 publications

RETRACTED: The herpesvirus glycoproteins B and H·L are sequentially recruited to the receptor-bound gD to effect membrane fusion at virus entry

RETRACTED: The herpesvirus glycoproteins B and H·L are sequentially recruited to the receptor-bound gD to effect membrane fusion at virus entry

Herpes simplex virus type 1 mediates fusion through a hemifusion intermediate by sequential activity of glycoproteins D, H, L, and B

N- and C-terminal external domains of human herpesvirus-6 glycoprotein H affect a fusion-associated conformation mediated by glycoprotein L binding the N terminus.

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