A Randomized Trial of Hyperimmune Globulin to Prevent Congenital Cytomegalovirus

Revello, Maria Grazia; Lazzarotto, Tiziana; Guerra, Brunella; Spinillo, Arsenio; Ferrazzi, E.; Kustermann, Alessandra; Guaschino, Secondo; Vergani, Patrizia; Todros, Tullia; Frusca, T.; Arossa, Alessia; Furione, Milena; Rognoni, Vanina; Rizzo, Nicola; Gabrielli, Liliana; Klersy, Catherine; Gerna, Giuseppe

doi:10.1097/01.ogx.0000452701.59180.cd

Cited by 64 publications

(103 citation statements)

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“…The initial studies claimed that hyperimmune globulin preparations were effective in protecting foetuses from HCMV transmission and disease during primary infection of HCMV-seronegative mothers [69]. However, a subsequent double-blind placebo-controlled study reported a nonsignificant reduction in the rate of congenital infections between a group of pregnant women receiving placebo and one receiving hyperimmune globulin [70].…”

Section: Antibody Response To Pc and The Other Glycoprotein Complexesmentioning

confidence: 99%

The pentameric complex of human Cytomegalovirus: cell tropism, virus dissemination, immune response and vaccine development

Gerna

Revello

Baldanti

et al. 2017

Journal of General Virology

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Between the 1980s and 1990s, three assays were developed for diagnosis of human cytomegalovirus (HCMV) infections: leuko (L)-antigenemia, L-viremia and L-DNAemia, detecting viral protein pp65, infectious virus and viral DNA, respectively, in circulating leukocytes Repeated initial attempts to reproduce the three assays in vitro using laboratory-adapted strains and infected cell cultures were consistently unsuccessful. Results were totally reversed when wild-type HCMV strains were used to infect either fibroblasts or endothelial cells. Careful analysis and sequencing of plaque-purified viruses from recent clinical isolates drew attention to the ULb¢ region of the HCMV genome. Using bacterial artificial chromosome technology, it was shown by both gain-of-function and loss-of-function experiments that UL131-128 genes are indispensable for virus growth in endothelial cells and virus transfer to leukocytes. In addition, a number of clinical isolates passaged in human fibroblasts had lost both properties (leuko-tropism and endothelial cell-tropism) when displaying a mutation in the UL131-128 locus

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Section: Antibody Response To Pc and The Other Glycoprotein Complexesmentioning

confidence: 99%

The pentameric complex of human Cytomegalovirus: cell tropism, virus dissemination, immune response and vaccine development

Gerna

Revello

Baldanti

et al. 2017

Journal of General Virology

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“…121 Lastly, it should be noted that a recently reported, well controlled trial of human hyperimmune globuline to prevent intrauterine HCMV transmission demonstrate no efficacy of this approach. 122 The proposed mechanisms of protection are virus neutralization, with proteins in the gH/gL/UL128/UL130/ UL131 complex being the major targets of neutralizing antibodies, reduction of placental inflammation and perhaps reduction in the cytokine-mediated cellular immune response. 123,124 Although antibodies play an important role in protection against CMV infection and disease, the level of protection is incomplete.…”

Section: Antibody-mediated Immunity To CMV Infectionmentioning

confidence: 99%

Immunobiology of congenital cytomegalovirus infection of the central nervous system—the murine cytomegalovirus model

et al. 2014

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Congenital human cytomegalovirus infection is a leading infectious cause of long-term neurodevelopmental sequelae, including mental retardation and hearing defects. Strict species specificity of cytomegaloviruses has restricted the scope of studies of cytomegalovirus infection in animal models. To investigate the pathogenesis of congenital human cytomegalovirus infection, we developed a mouse cytomegalovirus model that recapitulates the major characteristics of central nervous system infection in human infants, including the route of neuroinvasion and neuropathological findings. Following intraperitoneal inoculation of newborn animals with mouse cytomegalovirus, the virus disseminates to the central nervous system during high-level viremia and replicates in the brain parenchyma, resulting in a focal but widespread, non-necrotizing encephalitis. Central nervous system infection is coupled with the recruitment of resident and peripheral immune cells as well as the expression of a large number of pro-inflammatory cytokines. Although infiltration of cellular constituents of the innate immune response characterizes the early immune response in the central nervous system, resolution of productive infection requires virus-specific CD8 1 T cells. Perinatal mouse cytomegalovirus infection results in profoundly altered postnatal development of the mouse central nervous system and long-term motor and sensory disabilities. Based on an enhanced understanding of the pathogenesis of this infection, prospects for novel intervention strategies aimed to improve the outcome of congenital human cytomegalovirus infection are proposed.

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“…The current therapy for CMV disease is treatment with either ganciclovir or valganciclovir, which are associated with significant toxicity and not approved for use in pregnant women or for congenitally damaged infants (5). CMV hyperimmunoglobulin (CMV-HIG; pooled human IgG from CMV-positive individuals) has demonstrated efficacy in certain solid organ transplant recipients and more recently found to show limited success in protecting infants from congenital CMV disease (1,6,7). These findings suggest that more potent or differently targeted antibody therapy may prove to be an effective and safe alternative to the current forms of CMV therapy.…”

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confidence: 99%

Mechanism for neutralizing activity by the anti-CMV gH/gL monoclonal antibody MSL-109

Fouts¹,

Comps-Agrar²,

Stengel

et al. 2014

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

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Cytomegalovirus (CMV) is a widespread opportunistic pathogen that causes birth defects when transmitted transplacentally and severe systemic illness in immunocompromised individuals. MSL-109, a human monoclonal IgG isolated from a CMV seropositive individual, binds to the essential CMV entry glycoprotein H (gH) and prevents infection of cells. Here, we suggest a mechanism for neutralization activity by MSL-109. We define a genetic basis for resistance to MSL-109 and have generated a structural model of gH that reveals the epitope of this neutralizing antibody. Using surface-based, time-resolved FRET, we demonstrate that gH/gL interacts with glycoprotein B (gB). Additionally, we detect homodimers of soluble gH/gL heterodimers and confirm this novel oligomeric assembly on full-length gH/gL expressed on the cell surface. We show that MSL-109 perturbs the dimerization of gH/gL:gH/gL, suggesting that dimerization of gH/gL may be required for infectivity. gH/gL homodimerization may be conserved between alpha-and betaherpesviruses, because both CMV and HSV gH/gL demonstrate self-association in the FRET system. This study provides evidence for a novel mechanism of action for MSL-109 and reveals a previously undescribed aspect of viral entry that may be susceptible to therapeutic intervention.H uman CMV is a β-group herpesvirus that causes severe complications in immunocompromised individuals. CMV infects between 60% and 80% of the adult population worldwide (1). As with other herpesviruses, CMV establishes a lifelong latency in the host but is largely asymptomatic among infected immunocompetent individuals (2). However, during severe immunosuppression (e.g., in the setting of hematopoietic stem cell transplantation and solid organ transplantation, or advanced HIV/AIDS), CMV reactivation or primary infection can result in life-threatening disease. In addition, the acquisition of primary CMV infection during pregnancy, although of little consequence to the mother, can have severe clinical consequences in the developing fetus (3, 4). The current therapy for CMV disease is treatment with either ganciclovir or valganciclovir, which are associated with significant toxicity and not approved for use in pregnant women or for congenitally damaged infants (5). CMV hyperimmunoglobulin (CMV-HIG; pooled human IgG from CMV-positive individuals) has demonstrated efficacy in certain solid organ transplant recipients and more recently found to show limited success in protecting infants from congenital CMV disease (1, 6, 7). These findings suggest that more potent or differently targeted antibody therapy may prove to be an effective and safe alternative to the current forms of CMV therapy.Like other herpesviruses, CMV uses multiprotein entry complexes to initiate infection of host cells. Three glycoproteins, gB, gH, and gL, known as the "core fusion machinery," are conserved in all herpesviruses and are required for entry (8,9). gB, the most conserved of these glycoproteins, exists as a homotrimer and catalyzes membrane fusion during vira...

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A Randomized Trial of Hyperimmune Globulin to Prevent Congenital Cytomegalovirus

Cited by 64 publications

References 10 publications

The pentameric complex of human Cytomegalovirus: cell tropism, virus dissemination, immune response and vaccine development

The pentameric complex of human Cytomegalovirus: cell tropism, virus dissemination, immune response and vaccine development

Immunobiology of congenital cytomegalovirus infection of the central nervous system—the murine cytomegalovirus model

Mechanism for neutralizing activity by the anti-CMV gH/gL monoclonal antibody MSL-109

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