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Antibodies Targeting KSHV gH/gL Reveal Distinct Neutralization Mechanisms

Kaposi’s sarcoma herpesvirus (KSHV) is associated with a significant disease burden, in particular in Sub-Sahara Africa. A KSHV vaccine would be highly desirable, but the mechanisms underlying neutralizing antibody responses against KSHV remain largely unexplored. The complex made of glycoproteins H...

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Autores principales: Fricke, Thomas, Großkopf, Anna K., Ensser, Armin, Backovic, Marija, Hahn, Alexander S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8953146/
https://www.ncbi.nlm.nih.gov/pubmed/35336948
http://dx.doi.org/10.3390/v14030541
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author Fricke, Thomas
Großkopf, Anna K.
Ensser, Armin
Backovic, Marija
Hahn, Alexander S.
author_facet Fricke, Thomas
Großkopf, Anna K.
Ensser, Armin
Backovic, Marija
Hahn, Alexander S.
author_sort Fricke, Thomas
collection PubMed
description Kaposi’s sarcoma herpesvirus (KSHV) is associated with a significant disease burden, in particular in Sub-Sahara Africa. A KSHV vaccine would be highly desirable, but the mechanisms underlying neutralizing antibody responses against KSHV remain largely unexplored. The complex made of glycoproteins H and L (gH/gL) activates gB for the fusion of viral and cellular membranes in all herpesviruses. KSHV gH/gL also interacts with cellular Eph family receptors. To identify optimal antigens for vaccination and to elucidate neutralization mechanisms, we primed mice with recombinantly expressed, soluble gH/gL (gHecto/gL) that was either wildtype (WT), lacking defined glycosylation sites or bearing modified glycosylation, followed by boosts with WT gHecto/gL. We also immunized with a gL-gHecto fusion protein or a gHecto-ferritin/gL nanoparticle. Immune sera neutralized KSHV and inhibited EphA2 receptor binding. None of the regimens was superior to immunization with WT gHecto/gL with regard to neutralizing activity and EphA2 blocking activity, the gL-gHecto fusion protein was equally effective, and the ferritin construct was inferior. gH/gL-targeting sera inhibited gB-mediated membrane fusion and inhibited infection also independently from receptor binding and gL, as demonstrated by neutralization of a novel KSHV mutant that does not or only marginally incorporate gL into the gH/gL complex and infects through an Eph-independent route.
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spelling pubmed-89531462022-03-26 Antibodies Targeting KSHV gH/gL Reveal Distinct Neutralization Mechanisms Fricke, Thomas Großkopf, Anna K. Ensser, Armin Backovic, Marija Hahn, Alexander S. Viruses Article Kaposi’s sarcoma herpesvirus (KSHV) is associated with a significant disease burden, in particular in Sub-Sahara Africa. A KSHV vaccine would be highly desirable, but the mechanisms underlying neutralizing antibody responses against KSHV remain largely unexplored. The complex made of glycoproteins H and L (gH/gL) activates gB for the fusion of viral and cellular membranes in all herpesviruses. KSHV gH/gL also interacts with cellular Eph family receptors. To identify optimal antigens for vaccination and to elucidate neutralization mechanisms, we primed mice with recombinantly expressed, soluble gH/gL (gHecto/gL) that was either wildtype (WT), lacking defined glycosylation sites or bearing modified glycosylation, followed by boosts with WT gHecto/gL. We also immunized with a gL-gHecto fusion protein or a gHecto-ferritin/gL nanoparticle. Immune sera neutralized KSHV and inhibited EphA2 receptor binding. None of the regimens was superior to immunization with WT gHecto/gL with regard to neutralizing activity and EphA2 blocking activity, the gL-gHecto fusion protein was equally effective, and the ferritin construct was inferior. gH/gL-targeting sera inhibited gB-mediated membrane fusion and inhibited infection also independently from receptor binding and gL, as demonstrated by neutralization of a novel KSHV mutant that does not or only marginally incorporate gL into the gH/gL complex and infects through an Eph-independent route. MDPI 2022-03-05 /pmc/articles/PMC8953146/ /pubmed/35336948 http://dx.doi.org/10.3390/v14030541 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Fricke, Thomas
Großkopf, Anna K.
Ensser, Armin
Backovic, Marija
Hahn, Alexander S.
Antibodies Targeting KSHV gH/gL Reveal Distinct Neutralization Mechanisms
title Antibodies Targeting KSHV gH/gL Reveal Distinct Neutralization Mechanisms
title_full Antibodies Targeting KSHV gH/gL Reveal Distinct Neutralization Mechanisms
title_fullStr Antibodies Targeting KSHV gH/gL Reveal Distinct Neutralization Mechanisms
title_full_unstemmed Antibodies Targeting KSHV gH/gL Reveal Distinct Neutralization Mechanisms
title_short Antibodies Targeting KSHV gH/gL Reveal Distinct Neutralization Mechanisms
title_sort antibodies targeting kshv gh/gl reveal distinct neutralization mechanisms
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8953146/
https://www.ncbi.nlm.nih.gov/pubmed/35336948
http://dx.doi.org/10.3390/v14030541
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