Chronic HIV‐1 Tat action induces HLA‐DR downregulation in B cells: A mechanism for lymphoma immune escape in people living with HIV
Résumé
Abstract Despite the success of combination antiretroviral therapy, people living with human immunodeficiency virus (HIV) still have an increased risk of Epstein−Barr virus (EBV)‐associated B cell malignancies. In the HIV setting, B cell physiology is altered by coexistence with HIV‐infected cells and the chronic action of secreted viral proteins, for example, HIV‐1 Tat that, once released, efficiently penetrates noninfected cells. We modeled the chronic action of HIV‐1 Tat on B cells by ectopically expressing Tat or TatC22G mutant in two lymphoblastoid B cell lines. The RNA‐sequencing analysis revealed that Tat deregulated the expression of hundreds of genes in B cells, including the downregulation of a subset of major histocompatibility complex (MHC) class II‐related genes. Tat‐induced downregulation of HLA‐DRB1 and HLA‐DRB5 genes led to a decrease in HLA‐DR surface expression; this effect was reproduced by coculturing B cells with Tat‐expressing T cells. Chronic Tat presence decreased the NF‐ᴋB pathway activity in B cells; this downregulated NF‐ᴋB‐dependent transcriptional targets, including MHC class II genes. Notably, HLA‐DRB1 and surface HLA‐DR expression was also decreased in B cells from people with HIV. Tat‐induced HLA‐DR downregulation in B cells impaired EBV‐specific CD4+ T cell response, which contributed to the escape from immune surveillance and could eventually promote B cell lymphomagenesis in people with HIV.
Mots clés
ANOVA
analysis of variance BL
Burkitt's lymphoma cART
combination antiretroviral therapy CFSE
carboxyfluorescein diacetate succinimydyl ester ChIP-qPCR
chromatin immunoprecipitation quantitative PCR DAPI
4′
6-diamidino-2-phenylindole Barr virus EGFP
enhanced green fluorescent protein GFP
green fluorescent protein GO
gene ontology GO BP
gene ontology biological process gp42
glycoprotein 42 HIV
human immunodeficiency virus IFNγ
interferon γ IGH
immunoglobulin heavy chain IKK
IκB kinase KEGG
Kyoto Encyclopedia major histocompatibility complex ORA
overrepresentation analysis PBMC
peripheral blood mononuclear cells PMA
phorbol-12-myristate-13-acetate P-TEFb
positive
analysis of variance
BL
Burkitt's lymphoma
cART
combination antiretroviral therapy
CFSE
carboxyfluorescein diacetate succinimydyl ester
ChIP-qPCR
chromatin immunoprecipitation quantitative PCR
DAPI
6-diamidino-2-phenylindole
Barr virus
EGFP
enhanced green fluorescent protein
GFP
green fluorescent protein
GO
gene ontology
GO BP
gene ontology biological process
gp42
glycoprotein 42
HIV
human immunodeficiency virus
IFNγ
interferon γ
IGH
immunoglobulin heavy chain
IKK
IκB kinase
KEGG
Kyoto Encyclopedia major histocompatibility complex
ORA
overrepresentation analysis
PBMC
peripheral blood mononuclear cells
PMA
phorbol-12-myristate-13-acetate
P-TEFb
Domaines
Sciences du Vivant [q-bio]| Origine | Publication financée par une institution |
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