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High EBV load and genomic diversity are associated with generation of gp350 specific neutralizing antibodies following Acute Infectious Mononucleosis.

High EBV load and genomic diversity are associated with generation of gp350 specific neutralizing antibodies following Acute Infectious Mononucleosis.
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Weiss ER, Alter G, Ogembo JG, Henderson JL, Tabak B, Bakiş Y, Somasundaran M, Garber M, Selin L, Luzuriaga K,


Weiss ER, Alter G, Ogembo JG, Henderson JL, Tabak B, Bakiş Y, Somasundaran M, Garber M, Selin L, Luzuriaga K, (click to view)

Weiss ER, Alter G, Ogembo JG, Henderson JL, Tabak B, Bakiş Y, Somasundaran M, Garber M, Selin L, Luzuriaga K,

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Journal of virology 2016 Oct 12() pii

Abstract

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 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 (convalescence, CONV). EBV gp350-specific IgG was detected in the sera of 17 (71%) of 24 individuals at AIM and all 24 (100%) individuals at 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 in AIM (4 of 24 individuals; 17%) but was commonly detected in CONV (19 of 24 individuals; 79%). The majority (83%) of samples taken during AIM neutralized infection of primary B cells; all samples obtained 6 months post-diagnosis neutralized EBV infection of cultured and primary target cells. Deep sequencing revealed inter-patient gp350 sequence variation, but conservation of the CR2 binding site. Levels of gp350-specific neutralizing activity directly correlated with higher peripheral blood EBV DNA levels in AIM and greater evolution of diversity in gp350 nucleotide sequences from AIM to CONV. In summary, we conclude that viral load and EBV gp350 diversity during early infection are associated with the development of neutralizing antibody responses following AIM.

IMPORTANCE
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 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 envelop 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.

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