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1.
Immunity ; 48(4): 799-811.e9, 2018 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-29669253

RESUMO

Epstein-Barr virus (EBV) is a causative agent of infectious mononucleosis and is associated with 200,000 new cases of cancer and 140,000 deaths annually. Subunit vaccines against this pathogen have focused on the gp350 glycoprotein and remain unsuccessful. We isolated human antibodies recognizing the EBV fusion machinery (gH/gL and gB) from rare memory B cells. One anti-gH/gL antibody, AMMO1, potently neutralized infection of B cells and epithelial cells, the two major cell types targeted by EBV. We determined a cryo-electron microscopy reconstruction of the gH/gL-gp42-AMMO1 complex and demonstrated that AMMO1 bound to a discontinuous epitope formed by both gH and gL at the Domain-I/Domain-II interface. Integrating structural, biochemical, and infectivity data, we propose that AMMO1 inhibits fusion of the viral and cellular membranes. This work identifies a crucial epitope that may aid in the design of next-generation subunit vaccines against this major public health burden.


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Infecções por Vírus Epstein-Barr/imunologia , Herpesvirus Humano 4/imunologia , Glicoproteínas de Membrana/imunologia , Proteínas do Envelope Viral/imunologia , Células 3T3 , Animais , Linfócitos B/virologia , Células CHO , Linhagem Celular , Cricetulus , Microscopia Crioeletrônica , Células Epiteliais/virologia , Epitopos de Linfócito B/imunologia , Células HEK293 , Humanos , Camundongos , Ligação Viral
2.
J Infect Dis ; 223(11): 1897-1904, 2021 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-33095855

RESUMO

BACKGROUND: Epstein-Barr virus (EBV) infection is a major cause of malignancy worldwide. Maternal antibody is thought to prevent EBV infection because it is uncommon in early infancy. Maternal HIV infection is associated with an increased incidence of EBV infection in exposed infants, which we hypothesized results from impaired transfer of EBV-neutralizing maternal antibodies. METHODS: Among Ugandan infants followed for EBV acquisition from birth, we measured antibody binding to EBV glycoproteins (gp350, gH/gL) involved in B-cell and epithelial-cell entry, as well as viral neutralization and antibody-dependent cellular cytotoxicity (ADCC) activity in plasma samples prior to infection. These serologic data were analyzed for differences between HIV-exposed uninfected (HEU) and HIV-unexposed (HUU) infants, and for associations with incident infant EBV infection. RESULTS: HEU infants had significantly higher titers than HUU infants for all EBV-binding and neutralizing antibodies measured (P < .01) but not ADCC activity, which was similar between groups. No antibody measure was associated with a decreased risk of EBV acquisition in the cohort. CONCLUSIONS: Our findings indicate that in this cohort maternal antibody did not protect infants against EBV infection through viral neutralization. The identification of protective nonneutralizing antibody functions would be invaluable for the development of an EBV vaccine.


Assuntos
Anticorpos Antivirais/imunologia , Infecções por Vírus Epstein-Barr , Infecções por HIV , Imunidade Materno-Adquirida , Infecções por Vírus Epstein-Barr/epidemiologia , Feminino , Infecções por HIV/complicações , Herpesvirus Humano 4 , Humanos , Lactente , Uganda/epidemiologia
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