Neutralizing activity of antibodies against the major herpes simplex virus type 1 glycoproteins

Eing, Bodo R.; Kühn, Joachim; Braun, Rüdiger W.

doi:10.1002/jmv.1890270113

Cited by 21 publications

(13 citation statements)

References 31 publications

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“…In the case of Herpesviridae and other complex viruses, the isolation of specific antibodies against potentially protective epitopes of surface glycoproteins is further complicated by the fact that the host humoral immune response is not restricted to determinants of the surface glycoproteins but is directed to all viral polypeptides (41 Immunoreactivity on Western blots of all antibodies to gD was preserved by boiling in the presence of SDS but not by exposure to 2-mercaptoethanol. Consistent with the notion that gB elicits conformationally sensitive antibodies (31), the immunoreactivities of 54-7 and 54-17 were eliminated by boiling in the presence of SDS, although they were resistant to exposure to SDS alone.…”

Section: Resultssupporting

confidence: 76%

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Directed selection of recombinant human monoclonal antibodies to herpes simplex virus glycoproteins from phage display libraries.

Sanna

Williamson

Logu

et al. 1995

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

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Human monoclonal antibodies have considerable potential in the prophylaxis and treatment of viral disease. However, only a few such antibodies suitable for clinical use have been produced to date. We have previously shown that large panels of human recombinant monoclonal antibodies against a plethora of infectious agents, including herpes simplex virus types 1 and 2, can be established from phage display libraries. Here we demonstrate that facile cloning of recombinant Fab fragments against specific viral proteins in their native conformation can be accomplished by panning phage display libraries against viral glycoproteins "captured" from infected cell extracts by specific monoclonal antibodies immobilized on ELISA plates. We have tested this strategy by isolating six neutralizing recombinant antibodies specific for herpes simplex glycoprotein gD or gB,

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Section: Resultssupporting

confidence: 76%

“…In good agreement with this model, neutralizing antibodies to gH, gB, and gD prevent membrane fusion but not virus attachment (25)(26)(27)30). Most of the protective responses to HSV both in man and in the murine model are directed to gD and gB (5,25,30,31 HSV-1 (strain F) and HSV-2 (strain G) were obtained from American Type Culture Collection.…”

mentioning

confidence: 99%

Directed selection of recombinant human monoclonal antibodies to herpes simplex virus glycoproteins from phage display libraries.

Sanna

Williamson

Logu

et al. 1995

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

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“…Little is known about the antibody repertoire in humans elicited by HSV glycoproteins during infection, although neutralizing activity against gD and gB has been documented in human sera (50,51). We examined the sera from 10 HSV-seropositive individuals who had been previously tested and classified according to their frequency of viral shedding (23).…”

Section: Discussionmentioning

confidence: 99%

Dissection of the Antibody Response against Herpes Simplex Virus Glycoproteins in Naturally Infected Humans

Cairns

Huang

Whitbeck

et al. 2014

J Virol

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Relatively little is known about the extent of the polyclonal antibody (PAb) repertoire elicited by herpes simplex virus (HSV) glycoproteins during natural infection and how these antibodies affect virus neutralization. Here, we examined IgGs from 10 HSV-seropositive individuals originally classified as high or low virus shedders. All PAbs neutralized virus to various extents. We determined which HSV entry glycoproteins these PAbs were directed against: glycoproteins gB, gD, and gC were recognized by all sera, but fewer sera reacted against gH/gL. We previously characterized multiple mouse monoclonal antibodies (MAbs) and mapped those with high neutralizing activity to the crystal structures of gD, gB, and gH/gL. We used a biosensor competition assay to determine whether there were corresponding human antibodies to those epitopes. All 10 samples had neutralizing IgGs to gD epitopes, but there were variations in which epitopes were seen in individual samples. Surprisingly, only three samples contained neutralizing IgGs to gB epitopes. To further dissect the nature of these IgGs, we developed a method to select out gD-and gB-specific IgGs from four representative sera via affinity chromatography, allowing us to determine the contribution of antibodies against each glycoprotein to the overall neutralization capacity of the serum. In two cases, gD and gB accounted for all of the neutralizing activity against HSV-2, with a modest amount of HSV-1 neutralization directed against gC. In the other two samples, the dominant response was to gD. IMPORTANCEAntibodies targeting functional epitopes on HSV entry glycoproteins mediate HSV neutralization. Virus-neutralizing epitopes have been defined and characterized using murine monoclonal antibodies. However, it is largely unknown whether these same epitopes are targeted by the humoral response to HSV infection in humans. We have shown that during natural infection, virusneutralizing antibodies are principally directed against gD, gB, and, to a lesser extent, gC. While several key HSV-neutralizing epitopes within gD and gB are commonly targeted by human serum IgG, others fail to induce consistent responses. These data are particularly relevant to the design of future HSV vaccines. Herpes simplex virus (HSV) infects the mouth, skin, eye, and genital regions. The hallmark of herpes simplex viruses is their ability to establish a lifelong latent or persistent infection in sensory neurons, with reactivations that cause recurrent disease or viral shedding without evidence of clinical symptoms. Currently, 16% of the United States population is seropositive for HSV-2 and 54% for HSV-1 (1). Although HSV-2 is typically the causative agent of genital lesions, there is an increased incidence of genital HSV-1 infection. Control and clearing of the virus and genital lesions have been ascribed to the generation of cellular immunity (2). Recently, Schiffer et al. (3) suggested that mucosal HSV-2-specific CD8 ϩ T cells represent containment of prior viral shedding rather than a correl...

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“…In addition to these four proteins, gC has been shown to play a critical role in virus attachment via heparan sulfate (23,24). In animal models, gC, gD, gH/gL, and gB stimulate a neutralizing Ab response (13,(25)(26)(27)(28)(29). gC also plays a critical role in immune evasion, acting as a complement receptor; immunization of animals with gC blocks this function (25,27,30,31).…”

mentioning

confidence: 99%

Patient-Specific Neutralizing Antibody Responses to Herpes Simplex Virus Are Attributed to Epitopes on gD, gB, or Both and Can Be Type Specific

Cairns

Huang

Gallagher

et al. 2015

J Virol

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Herpes simplex virus 1 (HSV-1) and HSV-2 infect many humans and establish a latent infection in sensory ganglia. Although some infected people suffer periodic recurrences, others do not. Infected people mount both cell-mediated and humoral responses, including the production of virus-neutralizing antibodies (Abs) directed at viral entry glycoproteins. Previously, we examined IgGs from 10 HSV-seropositive individuals; all neutralized virus and were directed primarily against gD or gD؉gB. Here, we expand our studies and examine 32 additional sera from HSV-infected individuals, 23 of whom had no recurrent disease. Using an Octet RED96 system, we screened all 32 serum samples directly for both glycoprotein binding and competition with known neutralizing anti-gD and -gB monoclonal Abs (MAbs). On average, the recurrent cohort exhibited higher binding to gD and gB and had higher neutralization titers. There were similar trends in the blocking of MAbs to critical gD and gB epitopes. When we depleted six sera of Abs to specific glycoproteins, we found different types of responses, but always directed primarily at gD and/or gB. Interestingly, in one dual-infected person, the neutralizing response to HSV-2 was due to gD2 and gB2, whereas HSV-1 neutralization was due to gD1 and gB1. In another case, virus neutralization was HSV-1 specific, with the Ab response directed entirely at gB1, despite this serum blocking type-common anti-gD and -gB neutralizing MAbs. These data are pertinent in the design of future HSV vaccines since they demonstrate the importance of both serotypes of gD and gB as immunogens. IMPORTANCEWe previously showed that people infected with HSV produce neutralizing Abs directed against gD or a combination of gD؉gB (and in one case, gD؉gB؉gC, which was HSV-1 specific). In this more extensive study, we again found that gD or gD؉gB can account for the virus neutralizing response and critical epitopes of one or both of these proteins are represented in sera of naturally infected humans. However, we also found that some individuals produced a strong response against gB alone. In addition, we identified type-specific contributions to HSV neutralization from both gD and gB. Contributions from the other entry glycoproteins, gC and gH/gL, were minimal and limited to HSV-1 neutralization. Knowing the variations in how humans see and mount a response to HSV will be important to vaccine development. Herpes simplex virus 1 (HSV-1) and HSV-2 cause human diseases, ranging from benign cold sores to life-threatening infections such as encephalitis and neonatal HSV disease (1, 2). The hallmark of HSV infection is the ability of each serotype to establish a lifelong latent infection in sensory neurons. Reactivation can lead to clinical symptoms such as oral or genital lesions. Currently, 47% of the U.S. population is seropositive for HSV-1 and 16% are seropositive for HSV-2 (3). Many seropositive individuals are asymptomatic, although a number of people shed virus regardless of clinical signs of disease (4). However,...

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Neutralizing activity of antibodies against the major herpes simplex virus type 1 glycoproteins

Cited by 21 publications

References 31 publications

Directed selection of recombinant human monoclonal antibodies to herpes simplex virus glycoproteins from phage display libraries.

Directed selection of recombinant human monoclonal antibodies to herpes simplex virus glycoproteins from phage display libraries.

Dissection of the Antibody Response against Herpes Simplex Virus Glycoproteins in Naturally Infected Humans

Patient-Specific Neutralizing Antibody Responses to Herpes Simplex Virus Are Attributed to Epitopes on gD, gB, or Both and Can Be Type Specific

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