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Evolution of functional antibodies following acute Epstein-Barr virus infection.

ABSTRACT: While Epstein-Barr virus causes mostly asymptomatic infection, associated malignancies, and autoimmune and lymphoproliferative diseases occur. To dissect the evolution of humoral immune responses over the course of EBV infection and to gain a better understanding of the potential contribution of antibody (Ab) function to viral control, we comprehensively profiled Ab specificities and Fc-functionalities using systems serology and VirScan. Ab functions against latent (EBNA1), early (p47/54) and two late (gp350/220 and VCA-p18) EBV proteins were overall modest and/or short-lived, differing from humoral responses induced during acute infection by other viruses such as HIV. In the first year post infection, only p18 elicited robust IgM-driven complement deposition and IgG-driven neutrophil phagocytosis while responses against EBNA-1 were largely Fc-functionally silent and only matured during chronic infection to drive phagocytosis. In contrast, Abs against Influenza virus readily mediated broad Fc-activity in all participants. These data suggest that EBV evades the induction of robust Fc-functional Abs, potentially due to the virus' life cycle, switching from lytic to latent stages during infection.

SUBMITTER: Karsten CB

PROVIDER: S-EPMC9481173 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Evolution of functional antibodies following acute Epstein-Barr virus infection.

Karsten Christina B CB Bartsch Yannic C YC Shin Sally A SA Slein Matthew D MD Heller Howard M HM Kolandaivelu Kumaran K Middeldorp Jaap M JM Alter Galit G Julg Boris B

PLoS pathogens 20220906 9

While Epstein-Barr virus causes mostly asymptomatic infection, associated malignancies, and autoimmune and lymphoproliferative diseases occur. To dissect the evolution of humoral immune responses over the course of EBV infection and to gain a better understanding of the potential contribution of antibody (Ab) function to viral control, we comprehensively profiled Ab specificities and Fc-functionalities using systems serology and VirScan. Ab functions against latent (EBNA1), early (p47/54) and tw ...[more]

PMID: 36067220

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Project description:The Epstein-Barr virus (EBV) gp350 glycoprotein interacts with the cellular receptor to mediate viral entry and is thought to be the major target for neutralizing antibodies. To better understand the role of EBV-specific antibodies in the control of viral replication and the evolution of sequence diversity, we measured EBV gp350-specific antibody responses and sequenced the gp350 gene in samples obtained from individuals experiencing primary EBV infection (acute infectious mononucleosis [AIM]) and again 6 months later (during convalescence [CONV]). EBV gp350-specific IgG was detected in the sera of 17 (71%) of 24 individuals at the time of AIM and all 24 (100%) individuals during CONV; binding antibody titers increased from AIM through CONV, reaching levels equivalent to those in age-matched, chronically infected individuals. Antibody-dependent cell-mediated phagocytosis (ADCP) was rarely detected during AIM (4 of 24 individuals; 17%) but was commonly detected during CONV (19 of 24 individuals; 79%). The majority (83%) of samples taken during AIM neutralized infection of primary B cells; all samples obtained at 6 months postdiagnosis neutralized EBV infection of cultured and primary target cells. Deep sequencing revealed interpatient gp350 sequence variation but conservation of the CR2-binding site. The levels of gp350-specific neutralizing activity directly correlated with higher peripheral blood EBV DNA levels during AIM and a greater evolution of diversity in gp350 nucleotide sequences from AIM to CONV. In summary, we conclude that the viral load and EBV gp350 diversity during early infection are associated with the development of neutralizing antibody responses following AIM. Antibodies against viral surface proteins can blunt the spread of viral infection by coating viral particles, mediating uptake by immune cells, or blocking interaction with host cell receptors, making them a desirable component of a sterilizing vaccine. The EBV surface protein gp350 is a major target for antibodies. We report the detection of EBV gp350-specific antibodies capable of neutralizing EBV infection in vitro The majority of gp350-directed vaccines focus on glycoproteins from lab-adapted strains, which may poorly reflect primary viral envelope diversity. We report some of the first primary gp350 sequences, noting that the gp350 host receptor binding site is remarkably stable across patients and time. However, changes in overall gene diversity were detectable during infection. Patients with higher peripheral blood viral loads in primary infection and greater changes in viral diversity generated more efficient antibodies. Our findings provide insight into the generation of functional antibodies, necessary for vaccine development.

Project description:BackgroundThe prospective application of plasma Epstein-Barr virus (EBV) DNA load as a noninvasive measure of intestinal EBV infection remains unexplored. This study aims to identify ideal threshold levels for plasma EBV DNA loads in the diagnosis and outcome prediction of intestinal EBV infection, particularly in cases of primary intestinal lymphoproliferative diseases and inflammatory bowel disease (IBD).MethodsReceiver operating characteristic (ROC) curves were examined to determine suitable thresholds for plasma EBV DNA load in diagnosing intestinal EBV infection and predicting its prognosis.Results108 patients were retrospectively assigned to the test group, while 56 patients were included in the validation group. Plasma EBV DNA loads were significantly higher in the intestinal EBV infection group compared to the non-intestinal EBV infection group (Median: 2.02 × 102 copies/mL, interquartile range [IQR]: 5.49 × 101-6.34×103 copies/mL versus 4.2×101 copies/mL, IQR: 1.07 ×101-6.08×101 copies/mL; P < 0.0001). Plasma EBV DNA levels at 9.21×101 and 6.77×101 copies/mL proved beneficial for the identification and prognostication in intestinal EBV infection, respectively. Values of 0.82 and 0.71 were yielded by the area under the ROC curve (AUC) in the test cohort, corresponding to sensitivities of 84.38% (95% confidence interval [95%CI]: 68.25%-93.14%) and 87.5% (95%CI: 69%-95.66%), specificities of 83.33% (95%CI: 64.15%-93.32%) and 68.09% (95%CI: 53.83%-79.6%), positive predictive values (PPV) of 87.1% (95%CI: 71.15%-94.87%) and 58.33% (95%CI: 42.2%-72.86%), and positive likelihood ratios (LR+) of 5.06 and 2.74 in the validation cohort, respectively. Furthermore, a plasma EBV DNA load of 5.4×102 copies/mL helped differentiate IBD with intestinal EBV infection from primary intestinal EBV-positive lymphoproliferative disorders (PIEBV+LPDs), achieving an AUC of 0.85 within the test cohort, as well as 85% sensitivity (95%CI: 63.96%-94.76%), 91.67% specificity (95%CI: 64.61%-99.57%), 94.44% PPV (95%CI: 74.24%-99.72%), and an LR+ of 10.2 in the validation cohort.ConclusionsPlasma EBV DNA load demonstrates notable potential in distinguishing between different patient cohorts with intestinal EBV infection, although its sensitivity requires further optimization for clinical application.

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Evolution of functional antibodies following acute Epstein-Barr virus infection.

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Evolution of functional antibodies following acute Epstein-Barr virus infection.

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