E4orf1 Suppresses E1B-Deleted Adenovirus Vaccine-Induced Immune Responses

VACCINES(2022)

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摘要
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 (Delta E1B Ad) are currently being explored for use in vaccine delivery. Delta E1B Ads are different from Ads with deletions in early region 1 and early region 3 (Delta E1/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 Delta E1B Ad. Here, we show that cells infected with an E1B55K and E4orf1-deleted (Delta E4(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, Delta E1B parental Ad that exhibited elevated levels of phosphorylated Akt. Rhesus macaques immunized with a Delta E4(1) Ad that expressed rhFLSC (HIV-1(BaL) gp120 linked to rhesus CD4 D1 and D2), exhibited higher levels of rhFLSC-specific interferon gamma-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 Delta E1B 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 Delta E1B Ad-based vaccines.
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关键词
adenovirus, HIV, vaccine, nonhuman primates, early region 4 open reading frame 1 (E4orf1), memory B-cells, antibody, cytokine genes, antibody neutralization, ADCC
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