Chronic HIV‐1 Tat action induces HLA‐DR downregulation in B cells: A mechanism for lymphoma immune escape in people living with HIV

• Published in: Journal of medical virology Vol. 96; no. 2; pp. e29423 - n/a
• Main Authors: Shmakova, Anna, Hugot, Coline, Kozhevnikova, Yana, Schwager (Karpukhina), Anna, Tsimailo, Ivan, Gérard, Laurence, Boutboul, David, Oksenhendler, Eric, Szewczyk‐Roszczenko, Olga, Roszczenko, Piotr, Buzun, Kamila, Sheval, Eugene V., Germini, Diego, Vassetzky, Yegor
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.02.2024
• Subjects: Antiretroviral agents; Antiretroviral therapy; B cells; B-Lymphocytes; CD4 antigen; CD4+ T cells; Deregulation; Down-Regulation; Drb1 protein; EBV; Epstein-Barr virus; Epstein-Barr Virus Infections; Gene expression; Gene sequencing; Genes; Herpesvirus 4, Human - genetics; Histocompatibility antigen HLA; HIV; HIV Infections - genetics; HIV-1 - genetics; HIV‐1; HLA-DRB1 Chains; Human immunodeficiency virus; Humans; Immunosurveillance; Lymphocytes; Lymphocytes B; Lymphocytes T; Lymphoma; Major histocompatibility complex; Malignancy; MHC class II; NF‐кB pathway; RNA‐sequencing; Sequence analysis; Tat; tat Gene Products, Human Immunodeficiency Virus - genetics; Tat protein; HIV-1; RNA-sequencing; Tat; EBV; B cells; CD4+ T cells; MHC class II; NF-кB pathway
• ISSN: 0146-6615; 1096-9071
• DOI: 10.1002/jmv.29423

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.