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ARVs alter the methylation status of the  MEKKK1  gene promoter in acute treated Jurkat T cells with inflammatory outcomesInflammation is reduced in patients under going antiretroviral therapy; however the mechanism is not well understood. We investigated DNA methylation of the mitogen-activated protein kinase kinase kinase kinase 1 ( MEKKK1 ) gene promoter in Jurkat T cells to determine whether the antiretroviral drugs, lamivudine, tenofovir disoproxil fumarate, dolutegravir, TLD (a combination of TDF, 3TC and DTG) and efavirenz modify the methylation status of the  MEKKK1  gene – a known stimulus of inflammation.Acute antiretroviral treatments (24 h) were not cytotoxic to Jurkat T cells.  MEKKK1  promoter hypomethylation occurred in cells treated with 5-aza-2’-deoxycytidine (Aza), TDF and 3TC, and  MEKKK1  promoter hypermethylation occurred in cells treated with DTG; however, promoter DNA methylation of the  MEKKK1  gene did not influence  MEKKK1  gene expression; therefore, these drugs did not epigenetically regulate  MEKKK1  and downstream signalling by promoter DNA methylation. Acute TLD and EFV treatments induced inflammation in Jurkat T cells by increasing MEKKK1, MAPK/ERK and NFκB expression, and activating  tumour necrosis factor-α  ( TNF-α ) expression. ARVs decreased  IL-10  gene expression, showing no anti-inflammatory activity.The data shows that the inflammation caused by ARVs is not related to the methylation status of  MEKKK1  gene promoter and suggests an alternative stimulus  via  post-transcriptional/post-translational modifications may activate the canonical MEKKK1/NFκB pathway that leads to inflammation. Finally, an increase in NFκB activity and pro-inflammatory cytokine activation seemed to occur  via  the MAPK/ERK pathway following ARV treatments in Jurkat T cells. Inflammation is reduced in patients under going antiretroviral therapy; however the mechanism is not well understood. We investigated DNA methylation of the mitogen-activated protein kinase kinase kinase kinase 1 ( MEKKK1 ) gene promoter in Jurkat T cells to determine whether the antiretroviral drugs, lamivudine, tenofovir disoproxil fumarate, dolutegravir, TLD (a combination of TDF, 3TC and DTG) and efavirenz modify the methylation status of the  MEKKK1  gene – a known stimulus of inflammation. Acute antiretroviral treatments (24 h) were not cytotoxic to Jurkat T cells.  MEKKK1  promoter hypomethylation occurred in cells treated with 5-aza-2’-deoxycytidine (Aza), TDF and 3TC, and  MEKKK1  promoter hypermethylation occurred in cells treated with DTG; however, promoter DNA methylation of the  MEKKK1  gene did not influence  MEKKK1  gene expression; therefore, these drugs did not epigenetically regulate  MEKKK1  and downstream signalling by promoter DNA methylation. Acute TLD and EFV treatments induced inflammation in Jurkat T cells by increasing MEKKK1, MAPK/ERK and NFκB expression, and activating  tumour necrosis factor-α  ( TNF-α ) expression. ARVs decreased  IL-10  gene expression, showing no anti-inflammatory activity. The data shows that the inflammation caused by ARVs is not related to the methylation status of  MEKKK1  gene promoter and suggests an alternative stimulus  via  post-transcriptional/post-translational modifications may activate the canonical MEKKK1/NFκB pathway that leads to inflammation. Finally, an increase in NFκB activity and pro-inflammatory cytokine activation seemed to occur  via  the MAPK/ERK pathway following ARV treatments in Jurkat T cells.

The effect of ARVs on the MEKKK1 gene promoter, inflammatory cytokine expression and signalling in acute treated Jurkat T cells