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E4orf1 Suppresses E1B-Deleted Adenovirus Vaccine-Induced Immune Responses
As demonstrated by the recent COVID pandemic, vaccines can reduce the burden arising from infectious agents. Adenoviruses (Ads) with deletion of the early region 1B55K (ΔE1B Ad) are currently being explored for use in vaccine delivery. ΔE1B Ads are different from Ads with deletions in early region 1...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8875587/ https://www.ncbi.nlm.nih.gov/pubmed/35214753 http://dx.doi.org/10.3390/vaccines10020295 |
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author | Sangare, Kotou Helmold Hait, Sabrina Moore, Madison Hogge, Christopher Hoang, Tanya Rahman, Mohammad Arif Venzon, David J. LaBranche, Celia Montefiori, David Robert-Guroff, Marjorie Thomas, Michael A. |
author_facet | Sangare, Kotou Helmold Hait, Sabrina Moore, Madison Hogge, Christopher Hoang, Tanya Rahman, Mohammad Arif Venzon, David J. LaBranche, Celia Montefiori, David Robert-Guroff, Marjorie Thomas, Michael A. |
author_sort | Sangare, Kotou |
collection | PubMed |
description | As demonstrated by the recent COVID pandemic, vaccines can reduce the burden arising from infectious agents. Adenoviruses (Ads) with deletion of the early region 1B55K (ΔE1B Ad) are currently being explored for use in vaccine delivery. ΔE1B Ads are different from Ads with deletions in early region 1 and early region 3 (ΔE1/E3) used in most Ad vaccine vectors in that they contain the Ad early region 1A (E1A), and therefore the ability to replicate. Common to almost all Ads that are being explored for clinical use is the Ad early region 4 (E4). Among the E4 genes is open reading frame 1 (E4orf1), which mediates signals through the PI3-kinase/Akt pathway that is known to modulate immune responses. This suggests that E4orf1 might also modulate immune responses, although it has remained unexplored in ΔE1B Ad. Here, we show that cells infected with an E1B55K and E4orf1-deleted (ΔE4(1)) Ad exhibited reduced levels of phosphorylated Akt (Ser473 and Thr308)) and expressed different intrinsic innate immune cytokines from those induced in cells infected with an E4orf1-containing, ΔE1B parental Ad that exhibited elevated levels of phosphorylated Akt. Rhesus macaques immunized with a ΔE4(1) Ad that expressed rhFLSC (HIV-1(BaL) gp120 linked to rhesus CD4 D1 and D2), exhibited higher levels of rhFLSC-specific interferon γ-producing memory T-cells, higher titers of rhFLSC-specific IgG1 binding antibody in serum, and antibodies able to mediate antibody-dependent cellular cytotoxicity (ADCC) with greater killing capacity than the ΔE1B Ad. Therefore, E4orf1, perhaps by acting through the PI3-kinase/Akt pathway, limits intrinsic innate and system-wide adaptive immune responses that are important for improved ΔE1B Ad-based vaccines. |
format | Online Article Text |
id | pubmed-8875587 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-88755872022-02-26 E4orf1 Suppresses E1B-Deleted Adenovirus Vaccine-Induced Immune Responses Sangare, Kotou Helmold Hait, Sabrina Moore, Madison Hogge, Christopher Hoang, Tanya Rahman, Mohammad Arif Venzon, David J. LaBranche, Celia Montefiori, David Robert-Guroff, Marjorie Thomas, Michael A. Vaccines (Basel) Article As demonstrated by the recent COVID pandemic, vaccines can reduce the burden arising from infectious agents. Adenoviruses (Ads) with deletion of the early region 1B55K (ΔE1B Ad) are currently being explored for use in vaccine delivery. ΔE1B Ads are different from Ads with deletions in early region 1 and early region 3 (ΔE1/E3) used in most Ad vaccine vectors in that they contain the Ad early region 1A (E1A), and therefore the ability to replicate. Common to almost all Ads that are being explored for clinical use is the Ad early region 4 (E4). Among the E4 genes is open reading frame 1 (E4orf1), which mediates signals through the PI3-kinase/Akt pathway that is known to modulate immune responses. This suggests that E4orf1 might also modulate immune responses, although it has remained unexplored in ΔE1B Ad. Here, we show that cells infected with an E1B55K and E4orf1-deleted (ΔE4(1)) Ad exhibited reduced levels of phosphorylated Akt (Ser473 and Thr308)) and expressed different intrinsic innate immune cytokines from those induced in cells infected with an E4orf1-containing, ΔE1B parental Ad that exhibited elevated levels of phosphorylated Akt. Rhesus macaques immunized with a ΔE4(1) Ad that expressed rhFLSC (HIV-1(BaL) gp120 linked to rhesus CD4 D1 and D2), exhibited higher levels of rhFLSC-specific interferon γ-producing memory T-cells, higher titers of rhFLSC-specific IgG1 binding antibody in serum, and antibodies able to mediate antibody-dependent cellular cytotoxicity (ADCC) with greater killing capacity than the ΔE1B Ad. Therefore, E4orf1, perhaps by acting through the PI3-kinase/Akt pathway, limits intrinsic innate and system-wide adaptive immune responses that are important for improved ΔE1B Ad-based vaccines. MDPI 2022-02-15 /pmc/articles/PMC8875587/ /pubmed/35214753 http://dx.doi.org/10.3390/vaccines10020295 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 Sangare, Kotou Helmold Hait, Sabrina Moore, Madison Hogge, Christopher Hoang, Tanya Rahman, Mohammad Arif Venzon, David J. LaBranche, Celia Montefiori, David Robert-Guroff, Marjorie Thomas, Michael A. E4orf1 Suppresses E1B-Deleted Adenovirus Vaccine-Induced Immune Responses |
title | E4orf1 Suppresses E1B-Deleted Adenovirus Vaccine-Induced Immune Responses |
title_full | E4orf1 Suppresses E1B-Deleted Adenovirus Vaccine-Induced Immune Responses |
title_fullStr | E4orf1 Suppresses E1B-Deleted Adenovirus Vaccine-Induced Immune Responses |
title_full_unstemmed | E4orf1 Suppresses E1B-Deleted Adenovirus Vaccine-Induced Immune Responses |
title_short | E4orf1 Suppresses E1B-Deleted Adenovirus Vaccine-Induced Immune Responses |
title_sort | e4orf1 suppresses e1b-deleted adenovirus vaccine-induced immune responses |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8875587/ https://www.ncbi.nlm.nih.gov/pubmed/35214753 http://dx.doi.org/10.3390/vaccines10020295 |
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