HIV-1 Tat is present in the serum of people living with HIV-1 despite viral suppression.

OBJECTIVES: Despite successful human immunodeficiency virus (HIV) control with combination antiretroviral therapy (cART), individuals with HIV still face health risks, including cancers, cardiovascular and neurocognitive diseases. An HIV protein, Tat, is potentially involved in these HIV-related diseases. Previous studies demonstrated circulating Tat in the blood of untreated people with HIV. Here, we measured Tat levels in the serum of cART-treated people with HIV to examine the effect of cART on Tat production. METHODS: Serum samples from 63 HIV-positive and 20 HIV-seronegative individuals were analyzed using an ELISA assay that detected Tat concentrations above 2.5 ng/mL. RESULTS: Among HIV-positive individuals, the Tat level ranged from 0 to 14 ng/mL. 25.4% (16 out of 63) exceeded the 2.5 ng/mL cut-off, with a median HIV Tat level of 4.518 [3.329-8.120] ng/mL. No correlation was revealed between Tat levels and CD4+ T cell counts, serum HIV RNA, p24 antigen, or anti-Tat levels. CONCLUSIONS: Despite cART, circulating HIV Tat persists and may contribute to HIV-related diseases. This emphasizes the need for further research on the mechanisms of Tat action in non-infected cells where it can penetrate upon circulation in the blood.

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

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.