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Utilizing the Antigen Capsid-Incorporation Strategy for the Development of Adenovirus Serotype 5-Vectored Vaccine Approaches
Published on: May 6, 2015
KIR3DS1 directs NK cell-mediated protection against human adenovirus infections
Johannes M Jung1,2, Wilhelm Ching2, Martin E Baumdick1
1Research Department Virus Immunology, Leibniz Institute for Experimental Virology, Hamburg, Germany.
Insights
Human adenoviruses (HAdVs) cause severe disease in children after stem cell transplants. A new study shows the KIR3DS1/HLA-F pathway enhances NK cell killing of HAdV-infected cells, offering a potential immunotherapy target.
Area of Science:
- Immunology
- Virology
- Transplantation
Background:
- Human adenoviruses (HAdVs) are a significant cause of disease in children, especially after allogeneic hematopoietic stem cell transplantation (allo-HSCT).
- Effective therapies for HAdV infections in immunocompromised individuals are limited.
- Understanding immune recognition of HAdV is crucial for developing new therapeutic strategies.
Purpose of the Study:
- To investigate immune recognition of HAdV infection.
- To identify novel targets for immune-mediated control of HAdV infections.
- To explore the role of the KIR3DS1/HLA-F axis in HAdV disease.
Main Methods:
- Utilized a 3D organoid system derived from primary human intestinal epithelial cells to model HAdV infection.
- Assessed the expression of HLA molecules (HLA-F, HLA-A, HLA-B) in infected organoids.
- Conducted immunogenetic analyses in a pediatric allo-HSCT cohort.
Main Results:
- Human adenovirus type 5 (HAdV5) infection led to strong upregulation of HLA-F, facilitating enhanced killing of infected cells by KIR3DS1+ NK cells.
- HAdV5 infection resulted in downregulation of HLA-A and HLA-B, indicating viral evasion mechanisms against CD8+ T cells.
- Children receiving KIR3DS1/HLA-Bw4 donor cells showed a reduced risk of severe HAdV disease and faster viral clearance post-allo-HSCT.
Conclusions:
- The KIR3DS1/HLA-F axis represents a promising target for immunotherapeutic interventions against severe HAdV disease.
- This pathway plays a critical role in NK cell-mediated control of HAdV infections in immunocompromised hosts.
- Findings provide a basis for developing novel strategies to combat HAdV infections post-transplantation.
Abstract:
Human adenoviruses (HAdVs) are a major cause for disease in children, in particular after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Currently, effective therapies for HAdV infections in immunocompromised hosts are lacking. To decipher immune recognition of HAdV infection and determine new targets for immune-mediated control, we used an HAdV infection 3D organoid system, based on primary human intestinal epithelial cells. HLA-F, the functional ligand for the activating NK cell receptor KIR3DS1, was strongly up-regulated and enabled enhanced killing of HAdV5-infected cells in organoids by KIR3DS1+ NK cells. In contrast, HLA-A and HLA-B were significantly down-regulated in HAdV5-infected organoids in response to adenoviral E3/glycoprotein19K, consistent with evasion from CD8+ T cells. Immunogenetic analyses in a pediatric allo-HSCT cohort showed a reduced risk to develop severe HAdV disease and faster clearance of HAdV viremia in children receiving KIR3DS1/HLA-Bw4 donor cells compared with children receiving non–KIR3DS1/HLA-Bw4 cells. These findings identify the KIR3DS1/HLA-F axis as a new target for immunotherapeutic strategies against severe HAdV disease.
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